Hexahydropyrano[3,4-d][1,3]Thiazin-2-Amine Compounds

ABSTRACT

The present invention provides compounds of Formula I, and the tautomers thereof, and the pharmaceutically acceptable salts of the compounds and tautomers, wherein the compounds have the structure 
     
       
         
         
             
             
         
       
     
     wherein the variables R 1 , R 2 , R 3 , R 4  and x are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

FIELD OF THE INVENTION

The present invention relates to small molecule inhibitors of β-siteamyloid precursor protein (APP) Cleaving Enzyme 1 (BACE1). Inparticular, this invention relates to inhibiting the production ofA-beta peptides that can contribute to the formation of neurologicaldeposits of amyloid protein, which may be applicable in the treatment ofAlzheimer's Disease (AD) and other neurodegenerative and/or neurologicaldisorders in mammals. In addition, this invention is related to thetreatment of diabetes and obesity in mammals, including humans.

BACKGROUND OF THE INVENTION

Dementia results from a wide variety of distinctive pathologicalprocesses. The most common pathological processes causing dementia areAlzheimer's disease (“AD”), cerebral amyloid angiopathy (“CM”) andprion-mediated diseases (see, e.g., Haan et al., Clin. Neurol.Neurosurg., 1990, 92(4):305-310; Glenner et al., J. Neurol. Sci., 1989,94:1-28). AD is a progressive, neurodegenerative disorder characterizedby memory impairment and cognitive dysfunction. AD affects nearly halfof all people past the age of 85, the most rapidly growing portion ofthe United States population. As such, the number of AD patients in theUnited States is expected to increase from about 4 million to about 14million by 2050.

The accumulation of amyloid-β (Aβ peptides) is believed to be one of theunderlying causes of Alzheimer's Disease (AD), which is the most commoncause of cognitive decline in the elderly (Hardy & Allsop, TrendsPharmacol Sci., 1991; 12(10):383-8; Selkoe, Behav. Brain Res., 2008;192(1):106-13). Aβ, the major protein constituent of amyloid plaques, isderived from sequential cleavage of the type I integral membraneprotein, amyloid precursor protein (APP) by two proteases, β- andγ-secretase. Proteolytic cleavage of APP by the β-site APP cleavingenzymes (BACE1 and BACE2) generates a soluble N-terminal ectodomain ofAPP (sAPPβ) and the C-terminal fragment C99. Subsequent cleavage of themembrane bound C99 fragment by the γ-secretase liberates the various Aβpeptide species, of which Aβ40 and Aβ42 are the most predominant forms(Vassar et al, J. Neurosci., 2009; 29(41):12787-94; Marks & Berg,Neurochem. Res., 2010; 35:181-210). Therefore, limiting the generationof Aβ directly through inhibition of BACE1 is one of the most attractiveapproaches for the treatment of AD, as BACE1 inhibitors couldeffectively inhibit the formation of all predominant Aβ peptides.

In addition, it has been determined that BACE1 knock-out mice hadmarkedly enhanced clearance of axonal and myelin debris from degeneratedfibers, accelerated axonal regeneration, and earlier reinnervation ofneuromuscular junctions compared with littermate controls. These datasuggest BACE1 inhibition as a therapeutic approach to accelerateregeneration and recovery after peripheral nerve damage. (See Farah etal., J. Neurosci., 2011, 31(15): 5744-5754).

Insulin resistance and impaired glucose homoeostasis are importantindicators of Type 2 diabetes and are early risk factors of AD. Inparticular, there is a higher risk of sporadic AD in patients with Type2 diabetes and AD patients are more prone to Type 2 diabetes (Butler,Diabetes, 53:474-481, 2004). Recently, it has also been proposed that ADshould be reconsidered as Type 3 Diabetes (de la Monte, J. Diabetes Sci.Technol., 2008; 2(6):1101-1113). Of special interest is the fact that ADand Type 2 diabetes share common pathogenic mechanisms and possiblytreatments (Park SA., J. Clin. Neurol., 2011; 7:10-18; Raffa, Br. J.Clin. Pharmacol 2011/71:3/365-376). Elevated plasma levels of Aβ, theproduct of BACE activities, were recently associated with hyperglycemiaand obesity in humans (see Meakin et al., Biochem J., 2012,441(1):285-96; Martins, Journal of Alzheimer's Disease, 8 (2005)269-282). Moreover, increased Aβ production prompts the onset of glucoseintolerance and insulin resistance in mice (Cózar-Castellano, Am. J.Physiol. Endocrinol. Metab., 302:E1373-E1380, 2012; Delibegovic,Diabetologia (2011) 54:2143-2151). Finally, it is also suggested thatcirculating Aβ could participate in the development of atherosclerosisin both humans and mice (De Meyer, Atherosclerosis 216 (2011) 54-58;Catapano, Atherosclerosis 210 (2010) 78-87; Roher, Biochimica etBiophysica Acta 1812 (2011) 1508-1514).

Therefore, it is believed that BACE1 levels may play a critical role inglucose and lipid homoeostasis in conditions of chronic nutrient excess.Specifically, BACE1 inhibitors may be potentially useful for increasinginsulin sensitivity in skeletal muscle and liver as illustrated by thefact that reduction in BACE1 decreases body weight, protects againstdiet-induced obesity and enhances insulin sensitivity in mice (seeMeakin et al., Biochem. J. 2012, 441(1):285-96). Of equal interest isthe identification of LRP1 as a BACE1 substrate and the potential linkto atherosclerosis (Strickland, Physiol. Rev., 88: 887-918, 2008; Hyman,J. Biol. Chem., Vol. 280, No. 18, 17777-17785, 2005).

Likewise, inhibition of BACE2 is proposed as a treatment of Type 2diabetes with the potential to preserve and restore β-cell mass andstimulate insulin secretion in pre-diabetic and diabetic patients.(WO2011/020806). BACE2 is a β-cell enriched protease that regulatespancreatic β cell function and mass and is a close homologue of BACE1.Pharmacological inhibition of BACE2 increases β-cell mass and function,leading to the stabilization of Tmem27. (See Esterhazy et al., CellMetabolism 2011, 14(3): 365-377). It is suggested that BACE2 inhibitorsare useful in the treatment and/or prevention of diseases associatedwith the inhibition of BACE2 (e.g., Type 2 diabetes, with the potentialto preserve and restore β-cell mass and stimulate insulin secretion inpre-diabetic and diabetic patients) (WO2011/020806).

Aminodihydrothiazine or thioamidine compounds are described inUS2009/0082560, WO 2009/091016 and WO 2010/038686 as useful inhibitorsof the 1-secretase enzyme. Co-pending PCT application,PCT/IB2012/054198, filed by Pfizer Inc on Aug. 17, 2012, also describesaminodihydrothiazine compounds that are useful inhibitors of the1-secretase enzyme. The present invention is directed to novelthioamidine compounds and their use in the treatment ofneurodegenerative diseases, including AD, as well as the treatment ofmetabolic diseases and conditions such as diabetes and obesity.

SUMMARY OF THE INVENTION

The present invention relates to:

(1) A compound of Formula I,

wherein

R¹ is hydrogen or methyl, wherein said methyl is optionally substitutedwith one to three substituents independently selected from halogen ormethoxy;

R² is C₁₋₆ alkyl, —(C(R⁵)₂)_(m)—(C₃₋₆ cycloalkyl), —(C(R⁵)₂)_(m)—(C₆₋₁₀aryl), —(C(R⁵)₂)_(m)—(5- to 10-membered heteroaryl) or—(C(R⁵)₂)_(t)—OR⁶; wherein said alkyl, cycloalkyl, aryl or heteroarylmoieties are optionally substituted with one to three substituentsindependently selected from halogen, C₁₋₆ alkyl, —CH₂F, —CHF₂, —CF₃, —CNor —OR⁷;

R³ is —(C(R⁵)₂)_(m)—(CN) or —(C(R⁵)₂)_(n)—(NHR⁷);

R⁴ is independently halogen, C₁₋₆ alkyl or C₁₋₆ alkoxy; wherein saidalkyl or alkoxy is optionally substituted with one to three fluoro;

R⁵ at each occurrence is independently hydrogen or C₁₋₃ alkyl, whereinsaid alkyl is optionally substituted with one to three halogen;

R⁶ is hydrogen, C₁₋₆ alkyl or —(C(R⁵)₂)_(n)—(C₆₋₁₀ aryl), wherein saidalkyl and aryl are optionally substituted with one to three substituentsindependently selected from halogen, C₁₋₃ alkyl, —CH₂F, —CHF₂, —CF₃, —CNor —OH;

R⁷ for each occurrence is hydrogen or C₁₋₆ alkyl, wherein said alkyl isoptionally substituted with one to three substituents independentlyselected from halogen or —C₁₋₆ alkoxy;

m for each occurrence is is 0, 1 or 2;

n for each occurrence is 1 or 2; and

t is 1 or 2; and

x is 0, 1, 2 or 3;

or a tautomer thereof or a pharmaceutically acceptable salt of saidcompound or tautomer.

(2) A pharmaceutical composition comprising a compound of the invention,or a tautomer thereof or a pharmaceutically acceptable salt of saidcompound or tautomer, or a solvate thereof, and a pharmaceuticallyacceptable vehicle, diluent or carrier;

(3) The pharmaceutical composition described herein for inhibitingproduction of amyloid-β protein and for inhibiting beta-site amyloidprecursor protein cleaving enzyme 1 (BACE1);

(4) The pharmaceutical composition described herein for treating aneurodegenerative disease and, in particular, Alzheimer's Disease;

(5) The pharmaceutical composition described herein for inhibiting BACEactivity for the therapeutic and/or prophylactic treatment of diseasesand disorders characterized by elevated β-amyloid levels, includingdiabetes or type 2 diabetes;

(6) The pharmaceutical composition described herein for increasinginsulin sensitivity in skeletal muscle and liver in a mammal, includinghumans;

(7) The pharmaceutical composition described herein for treating and/orpreventing obesity.

(8) A compound or tautomer thereof or pharmaceutically acceptable saltof said compound or tautomer, or the solvate thereof, wherein thecompound is selected from Examples 1-20, further described in Table 1;

(9) Methods of inhibiting BACE enzyme activity, by administering atherapeutically effective amount of a thioamidine compound of any of theembodiments of Formula I or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier, to a mammal or a patient inneed thereof.

(10) Methods for treating conditions or diseases of the central nervoussystem and neurological disorders in which the β-secretase enzyme isinvolved (such as migraine; epilepsy; Alzheimer's disease; Parkinson'sdisease; brain injury; stroke; cerebrovascular diseases (includingcerebral arteriosclerosis, cerebral amyloid angiopathy, hereditarycerebral hemorrhage, and brain hypoxia-ischemia); cognitive disorders(including amnesia, senile dementia, HIV-associated dementia,Alzheimer's disease, Huntington's disease, Lewy body dementia, vasculardementia, drug-related dementia, tardive dyskinesia, myoclonus,dystonia, delirium, Pick's disease, Creutzfeldt-Jacob disease, HIVdisease, Gilles de la Tourette's syndrome, epilepsy, muscular spasms anddisorders associated with muscular spasticity or weakness includingtremors, and mild cognitive impairment (“MCI”); mental deficiency(including spasticity, Down syndrome and fragile X syndrome); sleepdisorders (including hypersomnia, circadian rhythm sleep disorder,insomnia, parasomnia, and sleep deprivation) and psychiatric disorderssuch as anxiety (including acute stress disorder, generalized anxietydisorder, social anxiety disorder, panic disorder, post-traumatic stressdisorder, agoraphobia, and obsessive-compulsive disorder); factitiousdisorder (including acute hallucinatory mania); impulse controldisorders (including compulsive gambling and intermittent explosivedisorder); mood disorders (including bipolar I disorder, bipolar IIdisorder, mania, mixed affective state, major depression, chronicdepression, seasonal depression, psychotic depression, seasonaldepression, premenstrual syndrome (PMS) premenstrual dysphoric disorder(PDD), and postpartum depression); psychomotor disorder; psychoticdisorders (including schizophrenia, schizoaffective disorder,schizophreniform, and delusional disorder); drug dependence (includingnarcotic dependence, alcoholism, amphetamine dependence, cocaineaddiction, nicotine dependence, and drug withdrawal syndrome); eatingdisorders (including anorexia, bulimia, binge eating disorder,hyperphagia, obesity, compulsive eating disorders and pagophagia);sexual dysfunction disorders; urinary incontinence; neuronal damagedisorders (including ocular damage, retinopathy or macular degenerationof the eye, tinnitus, hearing impairment and loss, and brain edema),nerve injury treatment (including accelerating regeneration and recoveryafter peripheral nerve damage) and pediatric psychiatric disorders(including attention deficit disorder, attention deficit/hyperactivedisorder, conduct disorder, and autism) in a mammal, preferably a human,comprising administering to said mammal a therapeutically effectiveamount of a compound of Formula I or pharmaceutically acceptable saltthereof. The compounds of Formula I may also be useful for improvingmemory (both short-term and long-term) and learning ability. The textrevision of the fourth edition of the Diagnostic and Statistical Manualof Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association,Washington, D.C.) provides a diagnostic tool for identifying many of thedisorders described herein. The skilled artisan will recognize thatthere are alternative nomenclatures, nosologies, and classificationsystems for disorders described herein, including those as described inthe DMS-IV-TR, and that terminology and classification systems evolvewith medical scientific progress;

(11) Methods for treating a neurological disorder (such as migraine;epilepsy; Alzheimer's disease; Parkinson's disease; Niemann-Pick type C;brain injury; stroke; cerebrovascular disease; cognitive disorder; sleepdisorder) or a psychiatric disorder (such as anxiety; factitiousdisorder; impulse control disorder; mood disorder; psychomotor disorder;psychotic disorder; drug dependence; eating disorder; and pediatricpsychiatric disorder) in a mammal, preferably a human, comprisingadministering to said mammal a therapeutically effective amount of acompound of Formula I or pharmaceutically acceptable salt thereof;

(12) Methods for the treatment (e.g., delaying the progression or onset)of diabetes or diabetes-related disorders including Type 1 and Type 2diabetes, impaired glucose tolerance, insulin resistance, hyperglycemia,and diabetic complications such as atherosclerosis, coronary heartdisease, stroke, peripheral vascular disease, nephropathy, hypertension,neuropathy, and retinopathy;

(13) Methods for the treatment of obesity co-morbidities, such asmetabolic syndrome. Metabolic syndrome includes diseases, conditions ordisorders such as dyslipidemia, hypertension, insulin resistance,diabetes (e.g., Type 2 diabetes), coronary artery disease and heartfailure. For more detailed information on metabolic syndrome, see, e.g.,Zimmet, P. Z. et al., “The Metabolic Syndrome: Perhaps an EtiologicMystery but Far From a Myth—Where Does the International DiabetesFederation Stand?,” Medscape Diabetes & Endocrinology, 7(2), (2005); andAlberti, K. G. et al., “The Metabolic Syndrome—A New WorldwideDefinition,” Lancet, 366, 1059-62 (2005);

(14) Methods for the treatment of nonalcoholic fatty liver disease(NAFLD) and hepatic insulin resistance;

(15) Combination therapies wherein the compounds of this invention mayalso be used in conjunction with other pharmaceutical agents for thetreatment of the diseases, conditions and/or disorders described herein.Therefore, methods of treatment that include administering compounds ofthe present invention in combination with other pharmaceutical agentsare also provided;

All patents, patent applications and references referred to herein arehereby incorporated by reference in their entirety.

Other features and advantages of this invention will be apparent fromthis specification and the appendent claims which describe theinvention. It is to be understood that both the foregoing and thefollowing detailed description are exemplary only and are notrestrictive of the invention as claimed.

DETAILED DESCRIPTION OF THE INVENTION

The present invention may be understood more readily by reference to thefollowing detailed description of exemplary embodiments of the inventionand the examples included therein. It is to be understood that thisinvention is not limited to specific methods of synthesis, which may ofcourse vary. It is also to be understood that the terminology usedherein is for the purpose of describing particular embodiments only andis not intended to be limiting.

In this specification and in the claims that follow, reference will bemade to a number of terms that shall be defined to have the followingmeanings:

The term “alkyl” refers to a linear or branched-chain saturatedhydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbonby removal of a hydrogen); in one embodiment from one to six carbonatoms; and in another embodiment from one to four carbon atoms; and inanother embodiment one to three carbon atoms. Non-limiting examples ofsuch substituents include methyl, ethyl, propyl (including n-propyl andisopropyl), butyl (including n-butyl, isobutyl, sec-butyl andtert-butyl), pentyl, isoamyl, hexyl and the like.

In some instances, the number of carbon atoms in a hydrocarbylsubstituent (i.e., alkyl, cycloalkyl, etc.) is indicated by the prefix“C_(x)-C_(y)-” or “C_(x-y)”, wherein x is the minimum and y is themaximum number of carbon atoms in the substituent. Thus, for example,“C₁-C₆-alkyl” or “C₁₋₆ alkyl” refers to an alkyl substituent containingfrom 1 to 6 carbon atoms. Illustrating further, C₃-C₆-cycloalkyl orC₃₋₆-cycloalkyl refers to saturated cycloalkyl containing from 3 to 6carbon ring atoms.

The term “alkoxy” refers to a straight chain saturated alkyl or branchedchain saturated alkyl bonded through an oxygen atom. Non-limitingexamples of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, tertiary butoxy, and pentoxy.

The term “aryl” means a carbocyclic aromatic system containing one, twoor three rings wherein such rings may be fused. If the rings are fused,one of the rings must be fully unsaturated and the fused ring(s) may befully saturated, partially unsaturated or fully unsaturated. The term“fused” means that a second ring is present (i.e., attached or formed)by having two adjacent atoms in common (i.e., shared) with the firstring. The term “fused” is equivalent to the term “condensed”. The term“aryl” embraces aromatic radicals such as phenyl, naphthyl,tetrahydronaphthyl, indanyl, biphenyl, benzo[b][1,4]oxazin-3(4H)-onyl,2,3-dihydro-1H indenyl, and 1,2,3,4-tetrahydronaphthalenyl.

The term “cycloalkyl” refers to a nonaromatic ring that is fullyhydrogenated and exists as a single ring. Examples of such carbocyclicrings include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term “halo” or “halogen” refers to fluorine (which may be depictedas —F), chlorine (which may be depicted as —Cl), bromine (which may bedepicted as —Br), or iodine (which may be depicted as —I).

The term “heteroaryl” refers to an aromatic ring structure containingfrom 5 to 6 ring atoms in which at least one of the ring atoms is aheteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ringatoms being independently selected from the group consisting of carbon,oxygen, nitrogen, and sulfur. Examples of heteroaryl substituentsinclude 6-membered ring substituents such as pyridyl, pyrazyl,pyrimidinyl, and pyridazinyl; and 5-membered ring substituents such astriazolyl, imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl andisothiazolyl. In a group that has a heteroaryl substituent, the ringatom of the heteroaryl substituent that is bound to the group may be oneof the heteroatoms, or it may be a ring carbon atom. Similarly, if theheteroaryl substituent is in turn substituted with a group orsubstituent, the group or substituent may be bound to one of theheteroatoms, or it may be bound to a ring carbon atom. The term“heteroaryl” also includes pyridyl N-oxides and groups containing apyridine N-oxide ring. Further examples include furyl, thienyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyridin-2(1H)-onyl,pyridazin-2(1H)-onyl, pyrimidin-2(1H)-onyl, pyrazin-2(1H)-onyl,imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl,6,7-dihydro-5H-cyclopenta[b]pyridinyl,6,7-dihydro-5H-cyclopenta[c]pyridinyl,1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl,2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl,5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl,6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazolyl,5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridinyl,4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl,4,5,6,7-tetrahydro-1H-indazolyl and 4,5,6,7-tetrahydro-2H-indazolyl. Theheteroaryl can be further substituted as defined herein.

Examples of single-ring heteroaryls and heterocycloalkyls includefuranyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl,dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl,pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl,imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl,tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl,isothiazolidinyl, thiaoxadiazolyl, oxathiazolyl, oxadiazolyl (includingoxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, or1,3,4-oxadiazolyl), pyranyl (including 1,2-pyranyl or 1,4-pyranyl),dihydropyranyl, pyridinyl, piperidinyl, diazinyl (including pyridazinyl,pyrimidinyl, piperazinyl, triazinyl (including s-triazinyl, as-triazinyland v-triazinyl), oxazinyl (including 2H-1,2-oxazinyl, 6H-1,3-oxazinyl,or 2H-1,4-oxazinyl), isoxazinyl (including o-isoxazinyl orp-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (including2H-1,2,4-oxadiazinyl or 2H-1,2,5-oxadiazinyl), morpholinyl.

The term “heteroaryl” also includes fused ring systems having one or tworings wherein such rings may be fused, wherein fused is as definedabove. It is to be understood that if a carbocyclic or heterocyclicmoiety may be bonded or otherwise attached to a designated substratethrough differing ring atoms without denoting a specific point ofattachment, then all possible points are intended, whether through acarbon atom or, for example, a trivalent nitrogen atom. For example, theterm “pyridyl” means 2-, 3- or 4-pyridyl, the term “thienyl” means 2- or3-thienyl, and so forth.

In some instances, the number of atoms in a cyclic substituentcontaining one or more heteroatoms (i.e., heteroaryl orheterocycloalkyl) is indicated by the prefix “x- to y-membered”, whereinx is the minimum and y is the maximum number of atoms forming the cyclicmoiety of the substituent. Thus, for example, “5- to 6-memberedheteroaryl” refers to a heteroaryl containing from 5 to 6 atoms,including one or more heteroatoms, in the cyclic moiety of theheteroaryl. The heteroatoms for this invention are selected fromnitrogen, oxygen and sulfur.

If substituents are described as “independently” having more than onevariable, each instance of a substituent is selected independent of theother from the list of variables available. Each substituent thereforemay be identical to or different from the other substituent(s).

As used herein, the term “Formula I” may be hereinafter referred to as a“compound(s) of the invention,” “the present invention,” and “compoundof Formula I.” Such terms are also defined to include all forms of thecompound of Formula I, including hydrates, solvates, isomers,crystalline and non-crystalline forms, isomorphs, polymorphs, tautomersand metabolites thereof. For example, the compounds of the invention, orpharmaceutically acceptable salts thereof, may exist in unsolvated andsolvated forms. When the solvent or water is tightly bound, the complexwill have a well-defined stoichiometry independent of humidity. When,however, the solvent or water is weakly bound, as in channel solvatesand hygroscopic compounds, the water/solvent content will be dependenton humidity and drying conditions. In such cases, non-stoichiometry willbe the norm.

The compounds of the invention may exist as clathrates or othercomplexes.

Included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein the drug and host arepresent in stoichiometric or non-stoichiometric amounts. Also includedare complexes of the compounds of the invention containing two or moreorganic and/or inorganic components, which may be in stoichiometric ornon-stoichiometric amounts. The resulting complexes may be ionized,partially ionized, or non-ionized. For a review of such complexes, seeJ. Pharm. Sci., 64(8), 1269-1288 by Haleblian (August 1975).

The compounds of the invention have asymmetric carbon atoms. Thecarbon-carbon bonds of the compounds of the invention may be depictedherein using a solid line (______), a solid wedge (

), or a dotted wedge (

). The use of a solid line to depict bonds to asymmetric carbon atoms ismeant to indicate that all possible stereoisomers (e.g., specificenantiomers, racemic mixtures, etc.) at that carbon atom are included.The use of either a solid or dotted wedge to depict bonds to asymmetriccarbon atoms is meant to indicate that only the stereoisomer shown ismeant to be included. It is possible that compounds of Formula I maycontain more than one asymmetric carbon atom. In those compounds, theuse of a solid line to depict bonds to asymmetric carbon atoms is meantto indicate that all possible stereoisomers are meant to be included.For example, unless stated otherwise, it is intended that the compoundsof Formula I can exist as enantiomers and diastereomers or as racematesand mixtures thereof. The use of a solid line to depict bonds to one ormore asymmetric carbon atoms in a compound of Formula I and the use of asolid or dotted wedge to depict bonds to other asymmetric carbon atomsin the same compound is meant to indicate that a mixture ofdiastereomers is present.

Stereoisomers of Formula I include cis and trans isomers, opticalisomers such as R and S enantiomers, diastereomers, geometric isomers,rotational isomers, conformational isomers, and tautomers of thecompounds of the invention, including compounds exhibiting more than onetype of isomerism; and mixtures thereof (such as racemates anddiastereomeric pairs). Also included are acid addition or base additionsalts wherein the counterion is optically active, for example, D-lactateor L-lysine, or racemic, for example, DL-tartrate or DL-arginine.

When any racemate crystallizes, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer.

The compounds of Formula I may exhibit the phenomenon of tautomerism andare regarded as compounds of the invention. For example, the compoundsof Formula I may exist in several tautomeric forms, including the2-amino-dihydrothiazine form, la, and the 2-imino-tetrahydrothiazineform, Ib. All such tautomeric forms, and mixtures thereof, are includedwithin the scope of compounds of Formula I. Tautomers exist as mixturesof a tautomeric set in solution. In solid form, usually one tautomerpredominates. Even though one tautomer may be described, the presentinvention includes all tautomers of the compounds of Formula I and saltsthereof. Examples of tautomers are described by the compounds of FormulaIa′ and Ib′ and, collectively and generically, are referred to ascompounds of Formula I.

The compounds of this invention may be used in the form of salts derivedfrom inorganic or organic acids. Depending on the particular compound, asalt of the compound may be advantageous due to one or more of thesalt's physical properties, such as enhanced pharmaceutical stability indiffering temperatures and humidities, or a desirable solubility inwater or oil. In some instances, a salt of a compound also may be usedas an aid in the isolation, purification, and/or resolution of thecompound.

Where a salt is intended to be administered to a patient (as opposed to,for example, being used in an in vitro context), the salt preferably ispharmaceutically acceptable. The term “pharmaceutically acceptable salt”refers to a salt prepared by combining a compound of Formula I with anacid whose anion, or a base whose cation, is generally consideredsuitable for human consumption. Pharmaceutically acceptable salts areparticularly useful as products of the methods of the present inventionbecause of their greater aqueous solubility relative to the parentcompound. For use in medicine, the salts of the compounds of thisinvention are non-toxic “pharmaceutically acceptable salts.” Saltsencompassed within the term “pharmaceutically acceptable salts” refer tonon-toxic salts of the compounds of this invention, which are generallyprepared by reacting the free base with a suitable organic or inorganicacid.

Suitable pharmaceutically acceptable acid addition salts of thecompounds of the present invention when possible include those derivedfrom inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric,boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic,sulfonic, and sulfuric acids, and organic acids such as acetic,benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic,glycolic, isothionic, lactic, lactobionic, maleic, malic,methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic,tartaric, and trifluoroacetic acids. Suitable organic acids generallyinclude, for example, aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic, and sulfonic classes of organic acids.

Specific examples of suitable organic acids include acetate,trifluoroacetate, formate, propionate, succinate, glycolate, gluconate,digluconate, lactate, malate, tartrate, citrate, ascorbate, glucuronate,maleate, fumarate, pyruvate, aspartate, glutamate, benzoate,anthranilate, stearate, salicylate, p-hydroxybenzoate, phenylacetate,mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate,benzenesulfonate, pantothenate, toluenesulfonate,2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate,algenate, β-hydroxybutyrate, galactarate, galacturonate, adipate,alginate, butyrate, camphorate, camphorsulfonate,cyclopentanepropionate, dodecylsulfate, glycoheptanoate,glycerophosphate, heptanoate, hexanoate, nicotinate,2-naphthalesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate,picrate, pivalate, thiocyanate, and undecanoate.

Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof may includealkali metal salts, e.g., sodium or potassium salts; alkaline earthmetal salts, e.g., calcium or magnesium salts; and salts formed withsuitable organic ligands, e.g., quaternary ammonium salts. In anotherembodiment, base salts are formed from bases which form non-toxic salts,including aluminum, arginine, benzathine, choline, diethylamine,diolamine, glycine, lysine, meglumine, olamine, tromethamine and zincsalts.

Organic salts may be made from secondary, tertiary or quaternary aminesalts, such as tromethamine, diethylamine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine), and procaine. Basic nitrogen-containing groups maybe quaternized with agents such as lower alkyl (C₁-C₆) halides (e.g.,methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides),dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamylsulfates), long chain halides (e.g., decyl, lauryl, myristyl, andstearyl chlorides, bromides, and iodides), arylalkyl halides (e.g.,benzyl and phenethyl bromides), and others.

In one embodiment, hemisalts of acids and bases may also be formed, forexample, hemisulfate and hemicalcium salts.

Also within the scope of the present invention are so-called “prodrugs”of the compound of the invention. Thus, certain derivatives of thecompound of the invention that may have little or no pharmacologicalactivity themselves can, when administered into or onto the body, beconverted into the compound of the invention having the desiredactivity, for example, by hydrolytic cleavage. Such derivatives arereferred to as “prodrugs.” Further information on the use of prodrugsmay be found in “Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium Series (T. Higuchi and V. Stella) and “Bioreversible Carriersin Drug Design,” Pergamon Press, 1987 (ed. E. B. Roche, AmericanPharmaceutical Association). Prodrugs in accordance with the inventioncan, for example, be produced by replacing appropriate functionalitiespresent in the compounds of any of Formula I with certain moieties knownto those skilled in the art as “pro-moieties” as described, for example,in “Design of Prodrugs” by H. Bundgaard (Elsevier, 1985).

The present invention also includes isotopically labeled compounds,which are identical to those recited in Formula I, but for the fact thatone or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe present invention include isotopes of hydrogen, carbon, nitrogen,oxygen, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹¹C, ¹⁴C,¹⁵N, ¹⁸O, ¹⁷O, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds of thepresent invention, prodrugs thereof, and pharmaceutically acceptablesalts of said compounds or of said prodrugs which contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of this invention. Certain isotopically labeled compounds ofthe present invention, for example those into which radioactive isotopessuch as ³H and ¹⁴C are incorporated, are useful in drug and/or substratetissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e.,¹⁴C, isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labeled compounds of Formula I of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily available isotopicallylabeled reagent for a non-isotopically labeled reagent.

As used herein, “eating disorders” refer to illnesses in which thepatient suffers disturbances in his/her eating behaviors and relatedthoughts and emotions. Representative examples of obesity-related eatingdisorders include overeating, bulimia, binge-eating disorder, compulsivedieting, nocturnal sleep-related eating disorder, pica, Prader-Willisyndrome, and night-eating syndrome.

“Patient” refers to warm-blooded animals such as, for example, guineapigs, mice, rats, gerbils, cats, rabbits, dogs, cattle, goats, sheep,horses, monkeys, chimpanzees, and humans.

The term “pharmaceutically acceptable” means the substance orcomposition must be compatible, chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The term “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, delaying theprogression of, delaying the onset of, or preventing the disorder orcondition to which such term applies, or one or more symptoms of suchdisorder or condition. The term “treatment”, as used herein, unlessotherwise indicated, refers to the act of treating as “treating” isdefined immediately above. The term “treating” also includes adjuvantand neo-adjuvant treatment of a subject. For the avoidance of doubt,reference herein to “treatment” includes reference to curative,palliative and prophylactic treatment, and to the administration of amedicament for use in such treatment.

In one embodiment of compounds of Formula I, R³ is —(C(R⁵)₂)_(m)—(CN); mis 0 or 1; and R⁵ at each occurrence is hydrogen; or a tautomer thereofor a pharmaceutically acceptable salt of said compound or tautomer.

In another embodiment of compounds of Formula I, R³ is—(C(R⁵)₂)_(n)—(NHR⁷); n is 1; and R⁵ at each occurrence is hydrogen; ora tautomer thereof or a pharmaceutically acceptable salt of saidcompound or tautomer.

In another further embodiment of compounds of Formula I, R² is C₁₋₆alkyl, optionally substituted with one to three fluoro, or—(C(R⁵)₂)_(t)—OR⁶; wherein t is 1; R⁵ at each occurrence is hydrogen,and R⁶ is C₁₋₃ alkyl, optionally substituted with one to three fluoro,or —(C(R⁵)₂)_(n)—(C₆₋₁₀ aryl), wherein said aryl is optionallysubstituted with one to three substituents independently selected fromhalogen, C₁₋₆ alkyl, —CH₂F, —CHF₂, —CF₃, —CN or —OH; or a tautomerthereof or a pharmaceutically acceptable salt of said compound ortautomer.

In a further embodiment of compounds of Formula I, R⁶ is—(C(R⁵)₂)_(n)—(C₆₋₁₀ aryl), said aryl is phenyl optionally substitutedwith substituents independently selected from halogen, C₁₋₆ alkyl,—CH₂F, —CHF₂, —CF₃, —CN or —OH; n is 1; and R⁵ at each occurrence ishydrogen; or a tautomer thereof or a pharmaceutically acceptable salt ofsaid compound or tautomer.

In another embodiment, R² is —(C(R⁵)₂)_(m)—(C₃₋₆ cycloalkyl) or—(C(R⁵)₂)_(m)—(5- to 10-membered heteroaryl), wherein said cycloalkyl orheteroaryl is optionally substituted with halogen or C₁₋₆ alkyloptionally substituted with one to three fluoro; m is 0; and R⁵ at eachoccurrence is hydrogen; or a tautomer thereof or a pharmaceuticallyacceptable salt of said compound or tautomer.

In further embodiments, R⁴ is independently fluoro, chloro, methyl,ethyl, propyl, methoxy or ethoxy, wherein said methyl, ethyl and propylgroups are optionally substituted with one to three fluoro; and x is 0,1 or 2; or a tautomer thereof or a pharmaceutically acceptable salt ofsaid compound or tautomer.

In yet another embodiment, R¹ is hydrogen; R² is C₁₋₆ alkyl, C₃₋₆cycloalkyl, 5-membered heteroaryl or —CH₂—OR⁶; wherein said alkyl isoptionally substituted with one F; R³ is —CN or —CH₂—(NHR⁷); R⁴ isindependently halogen or C₁₋₆ alkoxy; R⁶ is hydrogen, C₁₋₆ alkyl, or—CH₂-phenyl; R⁷ is C₁₋₆ alkyl optionally substituted with one to threesubstituents independently selected from halogen or C₁₋₆ alkoxy; and xis 0, 1, or 2; or a tautomer thereof or a pharmaceutically acceptablesalt of said compound or tautomer.

In one embodiment, a compound of Formula I is represented by a compoundof Formula Ia

wherein R¹, R², and R⁴ are defined as described above, or a tautomerthereof or a pharmaceutically acceptable salt of said compound ortautomer.

In a further embodiment of the compound of Formula Ia, R⁴ isindependently fluoro, chloro, methyl, ethyl, propyl, methoxy, or ethoxy,wherein said methyl, ethyl and propyl groups are optionally substitutedwith one to three fluoro; and x is 0, 1 or 2; or a tautomer thereof or apharmaceutically acceptable salt of said compound or tautomer. In afurther embodiment, R² is methyl, optionally substituted with fluoro; R⁴is independently methoxy, chloro or fluoro; x is 0, 1 or 2; or atautomer thereof or a pharmaceutically acceptable salt of said compoundor tautomer.

In a further embodiment of a compound of Formula Ia, R² is—(C(R⁵)₂)_(m)—(5-membered heteroaryl); R⁴ is independently methoxy,chloro or fluoro; m is 0; and x is 0, 1 or 2; or a tautomer thereof or apharmaceutically acceptable salt of said compound or tautomer.

In a further embodiment of a compound of Formula Ia, R² is—(C(R⁵)₂)_(t)—OR⁶; R⁶ is hydrogen, methyl or —(C(R⁵)₂)_(n)—(C₆₋₁₀ aryl),wherein the aryl of R⁶ is phenyl optionally substituted withsubstituents independently selected from halogen, C₁₋₆ alkyl, —CH₂F,—CHF₂, —CF₃, —CN or —OH; R⁴ is independently methoxy, chloro or fluoro;x is 0, 1 or 2; n is 1; and t is 1; or a tautomer thereof or apharmaceutically acceptable salt of said compound or tautomer.

In a further embodiment of a compound of Formula Ia, R² is—(C(R⁵)₂)_(m)—(C₃₋₆ cycloalkyl), wherein said cycloalkyl is optionallysubstituted with halogen or C₁₋₆ alkyl optionally substituted with oneto three fluoro; R⁴ is independently methoxy, chloro or fluoro; m is 0or 1; and x is 0, 1 or 2; or a tautomer thereof or a pharmaceuticallyacceptable salt of said compound or tautomer. In a further embodiment,R² is cyclopropyl; and m is 0; or a tautomer thereof or apharmaceutically acceptable salt of said compound or tautomer.

In another embodiment of a compound of Formula I is represented by acompound of Formula Ib

wherein R¹, R², R⁴ and R⁷ are defined as described above; or a tautomerthereof or a pharmaceutically acceptable salt of said compound ortautomer.

In another embodiment, R⁷ for each occurrence is methyl optionallysubstituted with one to three fluoro; or a tautomer thereof or apharmaceutically acceptable salt of said compound or tautomer. Inanother embodiment, R² is C₁₋₃ alkyl, optionally substituted with one tothree fluoro; R⁴ is independently fluoro, chloro or methoxy; and x is 0,1 or 2; or a tautomer thereof or a pharmaceutically acceptable salt ofsaid compound or tautomer.

Yet another embodiment of the present invention is the compound ofFormula I in which R¹ is hydrogen or fluoromethyl; R² is methyl,fluoromethyl, or 1-methyl-1H-pyrazol-4-yl; and R³ is(2,2,2-trifluoroethyl)aminomethyl or (1-methoxypropan-2-yl)aminomethyl.

A further embodiment of the present invention is the compound of FormulaI in which R¹ is hydrogen or fluoromethyl; R² is methyl, fluoromethyl,or 1-methyl-1H-pyrazol-4-yl; R³ is (2,2,2-trifluoroethyl)aminomethyl or(1-methoxypropan-2-yl)aminomethyl; R⁴ is fluoro and x is 1 or 2.

Typically, a compound of the invention is administered in an amounteffective to treat a condition as described herein. The compounds of theinvention are administered by any suitable route in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. Therapeutically effective doses ofthe compounds required to treat the progress of the medical conditionare readily ascertained by one of ordinary skill in the art usingpreclinical and clinical approaches familiar to the medicinal arts.

The compounds of the invention may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, or buccal or sublingual administration may beemployed, by which the compound enters the blood stream directly fromthe mouth.

In another embodiment, the compounds of the invention may also beadministered directly into the blood stream, into muscle, or into aninternal organ. Suitable means for parenteral administration includeintravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular and subcutaneous. Suitable devices for parenteraladministration include needle (including microneedle) injectors,needle-free injectors and infusion techniques.

In another embodiment, the compounds of the invention may also beadministered topically to the skin or mucosa, that is, dermally ortransdermally. In another embodiment, the compounds of the invention canalso be administered intranasally or by inhalation. In anotherembodiment, the compounds of the invention may be administered rectallyor vaginally. In another embodiment, the compounds of the invention mayalso be administered directly to the eye or ear.

The dosage regimen for the compounds and/or compositions containing thecompounds is based on a variety of factors, including the type, age,weight, sex and medical condition of the patient; the severity of thecondition; the route of administration; and the activity of theparticular compound employed. Thus the dosage regimen may vary widely.Dosage levels of the order from about 0.01 mg to about 100 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions. In one embodiment, the total daily dose of acompound of the invention (administered in single or divided doses) istypically from about 0.01 to about 100 mg/kg. In another embodiment, thetotal daily dose of the compound of the invention is from about 0.1 toabout 50 mg/kg, and in another embodiment, from about 0.5 to about 30mg/kg (i.e., mg compound of the invention per kg body weight). In oneembodiment, dosing is from 0.01 to 10 mg/kg/day. In another embodiment,dosing is from 0.1 to 1.0 mg/kg/day. Dosage unit compositions maycontain such amounts or submultiples thereof to make up the daily dose.In many instances, the administration of the compound will be repeated aplurality of times in a day (typically no greater than 4 times).Multiple doses per day typically may be used to increase the total dailydose, if desired.

For oral administration, the compositions may be provided in the form oftablets containing from about 0.01 mg to about 500 mg of the activeingredient, or in another embodiment, from about 1 mg to about 100 mg ofactive ingredient. Intravenously, doses may range from about 0.1 toabout 10 mg/kg/minute during a constant rate infusion.

Suitable subjects according to the present invention include mammaliansubjects. Mammals according to the present invention include, but arenot limited to, canine, feline, bovine, caprine, equine, ovine, porcine,rodents, lagomorphs, primates, and the like, and encompass mammals inutero. In one embodiment, humans are suitable subjects. Human subjectsmay be of either gender and at any stage of development.

In another embodiment, the invention comprises the use of one or morecompounds of the invention for the preparation of a medicament for thetreatment of the conditions recited herein.

For the treatment of the conditions referred to above, the compound ofthe invention can be administered as compound per se. Alternatively,pharmaceutically acceptable salts are suitable for medical applicationsbecause of their greater aqueous solubility relative to the parentcompound.

In another embodiment, the present invention comprises pharmaceuticalcompositions. Such pharmaceutical compositions comprise a compound ofthe invention presented with a pharmaceutically acceptable carrier. Thecarrier can be a solid, a liquid, or both, and may be formulated withthe compound as a unit-dose composition, for example, a tablet, whichcan contain from 0.05% to 95% by weight of the active compounds. Acompound of the invention may be coupled with suitable polymers astargetable drug carriers. Other pharmacologically active substances canalso be present.

The compounds of the present invention may be administered by anysuitable route, preferably in the form of a pharmaceutical compositionadapted to such a route, and in a dose effective for the treatmentintended. The active compounds and compositions, for example, may beadministered orally, rectally, parenterally, or topically.

Oral administration of a solid dose form may be, for example, presentedin discrete units, such as hard or soft capsules, pills, cachets,lozenges, or tablets, each containing a predetermined amount of at leastone compound of the present invention. In another embodiment, the oraladministration may be in a powder or granule form. In anotherembodiment, the oral dose form is sub-lingual, such as, for example, alozenge. In such solid dosage forms, the compounds of Formula I areordinarily combined with one or more adjuvants. Such capsules or tabletsmay contain a controlled-release formulation. In the case of capsules,tablets, and pills, the dosage forms also may comprise buffering agentsor may be prepared with enteric coatings.

In another embodiment, oral administration may be in a liquid dose form.Liquid dosage forms for oral administration include, for example,pharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art (e.g.,water). Such compositions also may comprise adjuvants, such as wetting,emulsifying, suspending, flavoring (e.g., sweetening), and/or perfumingagents.

In another embodiment, the present invention comprises a parenteral doseform. “Parenteral administration” includes, for example, subcutaneousinjections, intravenous injections, intraperitoneal injections,intramuscular injections, intrasternal injections, and infusion.Injectable preparations (e.g., sterile injectable aqueous or oleaginoussuspensions) may be formulated according to the known art using suitabledispersing, wetting agents, and/or suspending agents.

In another embodiment, the present invention comprises a topical doseform. “Topical administration” includes, for example, transdermaladministration, such as via transdermal patches or iontophoresisdevices, intraocular administration, or intranasal or inhalationadministration. Compositions for topical administration also include,for example, topical gels, sprays, ointments, and creams. A topicalformulation may include a compound that enhances absorption orpenetration of the active ingredient through the skin or other affectedareas. When the compounds of this invention are administered by atransdermal device, administration will be accomplished using a patcheither of the reservoir and porous membrane type or of a solid matrixvariety. Typical formulations for this purpose include gels, hydrogels,lotions, solutions, creams, ointments, dusting powders, dressings,foams, films, skin patches, wafers, implants, sponges, fibers, bandagesand microemulsions. Liposomes may also be used. Typical carriers includealcohol, water, mineral oil, liquid petrolatum, white petrolatum,glycerin, polyethylene glycol and propylene glycol. Penetrationenhancers may be incorporated; see, for example, J. Pharm. Sci., 88(10),955-958, by Finnin and Morgan (October 1999).

Formulations suitable for topical administration to the eye include, forexample, eye drops wherein the compound of this invention is dissolvedor suspended in a suitable carrier. A typical formulation suitable forocular or aural administration may be in the form of drops of amicronized suspension or solution in isotonic, pH-adjusted, sterilesaline. Other formulations suitable for ocular and aural administrationinclude ointments, biodegradable (e.g., absorbable gel sponges,collagen) and non-biodegradable (e.g., silicone) implants, wafers,lenses and particulate or vesicular systems, such as niosomes orliposomes. A polymer such as cross-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example,hydroxypropyl methyl cellulose, hydroxyethyl cellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum,may be incorporated together with a preservative, such as benzalkoniumchloride. Such formulations may also be delivered by iontophoresis.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant. Formulations suitable for intranasal administration aretypically administered in the form of a dry powder (either alone, as amixture, for example, in a dry blend with lactose, or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler or as an aerosol sprayfrom a pressurized container, pump, spray, atomizer (preferably anatomizer using electrohydrodynamics to produce a fine mist), ornebulizer, with or without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Forintranasal use, the powder may comprise a bioadhesive agent, forexample, chitosan or cyclodextrin.

In another embodiment, the present invention comprises a rectal doseform. Such rectal dose form may be in the form of, for example, asuppository. Cocoa butter is a traditional suppository base, but variousalternatives may be used as appropriate.

Other carrier materials and modes of administration known in thepharmaceutical art may also be used. Pharmaceutical compositions of theinvention may be prepared by any of the well-known techniques ofpharmacy, such as effective formulation and administration procedures.The above considerations in regard to effective formulations andadministration procedures are well known in the art and are described instandard textbooks. Formulation of drugs is discussed in, for example,Hoover, John E., Remington's Pharmaceutical Sciences, Mack PublishingCo., Easton, Pa., 1975; Liberman et al., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds.,Handbook of Pharmaceutical Excipients (3^(rd) Ed.), AmericanPharmaceutical Association, Washington, 1999.

The compounds of the present invention can be used, alone or incombination with other therapeutic agents, in the treatment of variousconditions or disease states. The compound(s) of the present inventionand other therapeutic agent(s) may be may be administered simultaneously(either in the same dosage form or in separate dosage forms) orsequentially.

Two or more compounds may be administered simultaneously, concurrentlyor sequentially. Additionally, simultaneous administration may becarried out by mixing the compounds prior to administration or byadministering the compounds at the same point in time but at differentanatomic sites or using different routes of administration.

The phrases “concurrent administration,” “co-administration,”“simultaneous administration,” and “administered simultaneously” meanthat the compounds are administered in combination.

The present invention includes the use of a combination of a BACEinhibitor compound as provided in Formula I and one or more additionalpharmaceutically active agent(s). If a combination of active agents isadministered, then they may be administered sequentially orsimultaneously, in separate dosage forms or combined in a single dosageform. Accordingly, the present invention also includes pharmaceuticalcompositions comprising an amount of: (a) a first agent comprising acompound of Formula I or a pharmaceutically acceptable salt of thecompound; (b) a second pharmaceutically active agent; and (c) apharmaceutically acceptable carrier, vehicle or diluent.

The compounds of this invention may also be used in conjunction withother pharmaceutical agents for the treatment of the diseases,conditions and/or disorders described herein. Therefore, methods oftreatment that include administering compounds of the present inventionin combination with other pharmaceutical agents are also provided.Suitable pharmaceutical agents that may be used in combination with thecompounds of the present invention include, without limitation:

(i) anti-obesity agents (including appetite suppressants), includinggut-selective MTP inhibitors (e.g., lomitapide, usistapide, granotapide,dirlotapide, mitratapide, implitapide and CAS No. 913541-47-6), CCKaagonists (e.g.,N-benzyl-2-[4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide,described in PCT Publication No. WO 2005/116034 or US Publication No.2005-0267100 A1), 5-HT_(2c) agonists (e.g., lorcaserin), MCR4 agonists(e.g., compounds described in U.S. Pat. No. 6,818,658), lipaseinhibitors (e.g., Cetilistat), PYY₃₋₃₆ (as used herein “PYY₃₋₃₆”includes analogs, such as peglated PYY₃₋₃₆, e.g., those described in USPublication 2006/0178501), opioid antagonists (e.g., naltrexone),oleoyl-estrone (CAS No. 180003-17-2), obinepitide (TM30338), pramlintide(Symlin®), tesofensine (NS2330), leptin, bromocriptine, orlistat,AOD-9604 (CAS No. 221231-10-3) and sibutramine.

(ii) anti-diabetic agents, such as an acetyl-CoA carboxylase (ACC)inhibitor as described in WO2009144554, WO2003072197, WO2009144555 andWO2008065508, a diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitor,such as those described in WO09016462 or WO2010086820, AZD7687 orLCQ908, a diacylglycerol O-acyltransferase 2 (DGAT-2) inhibitor, amonoacylglycerol O-acyltransferase inhibitor, a phosphodiesterase(PDE)-10 inhibitor, an AMPK activator, a sulfonylurea (e.g.,acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide,glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide,tolazamide, and tolbutamide), a meglitinide, an α-amylase inhibitor(e.g., tendamistat, trestatin and AL-3688), an α-glucoside hydrolaseinhibitor (e.g., acarbose), an α-glucosidase inhibitor (e.g., adiposine,camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, andsalbostatin), a PPAR γ agonist (e.g., balaglitazone, ciglitazone,darglitazone, englitazone, isaglitazone, pioglitazone androsiglitazone), a PPAR α/γ agonist (e.g., CLX-0940, GW-1536, GW-1929,GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), a biguanide(e.g., metformin), a glucagon-like peptide 1 (GLP-1) modulator such asan agonist (e.g., exendin-3 and exendin-4), liraglutide, albiglutide,exenatide (Byetta®), albiglutide, taspoglutide, lixisenatide,dulaglutide, semaglutide, NN-9924, TTP-054, a protein tyrosinephosphatase-1B (PTP-1B) inhibitor [e.g., trodusquemine, hyrtiosalextract, and compounds disclosed by Zhang, S. et al., Drug DiscoveryToday, 12(9/10), 373-381 (2007)], a SIRT-1 inhibitor (e.g., resveratrol,GSK2245840 or GSK184072), a dipeptidyl peptidase IV (DPP-IV) inhibitor(e.g., those in WO2005116014, sitagliptin, vildagliptin, alogliptin,dutogliptin, linagliptin and saxagliptin), an insulin secretagogue, afatty acid oxidation inhibitor, an A2 antagonist, a c-jun amino-terminalkinase (JNK) inhibitor, a glucokinase activator (GKa) such as thosedescribed in WO2010103437, WO2010103438, WO2010013161, WO2007122482,TTP-399, TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658or GKM-001, insulin, an insulin mimetic, a glycogen phosphorylaseinhibitor (e.g., GSK1362885), a VPAC2 receptor agonist, an SGLT2inhibitor, such as those described in E. C. Chao et al., Nature ReviewsDrug Discovery 9, 551-559 (July 2010) including dapagliflozin,canagliflozin, BI-10733, tofogliflozin (CSG452), ASP-1941, THR1474,TS-071, ISIS388626 and LX4211, as well as those in WO2010023594, aglucagon receptor modulator such as those described in Demong, D. E. etal., Annual Reports in Medicinal Chemistry 2008, 43, 119-137, a GPR119modulator, particularly an agonist, such as those described inWO2010140092, WO2010128425, WO2010128414, WO2010106457, Jones, R. M. etal., in Medicinal Chemistry 2009, 44, 149-170 (e.g., MBX-2982,GSK1292263, APD597 and PSN821), an FGF21 derivative or an analog such asthose described in Kharitonenkov, A. et al., Current Opinion inInvestigational Drugs 2009, 10(4), 359-364, TGR5 (also termed GPBAR1)receptor modulators, particularly agonists, such as those described inZhong, M., Current Topics in Medicinal Chemistry, 2010, 10(4), 386-396and INT777, a GPR40 agonist, such as those described in Medina, J. C.,Annual Reports in Medicinal Chemistry, 2008, 43, 75-85, including butnot limited to TAK-875, a GPR120 modulator, particularly an agonist, ahigh affinity nicotinic acid receptor (HM74A) activator, and an SGLT1inhibitor, such as GSK1614235. A further representative listing ofanti-diabetic agents that can be combined with the compounds of thepresent invention can be found, for example, at page 28, line 35 throughpage 30, line 19 of WO2011005611. Preferred anti-diabetic agents aremetformin and DPP-IV inhibitors (e.g., sitagliptin, vildagliptin,alogliptin, dutogliptin, linagliptin and saxagliptin). Otherantidiabetic agents could include inhibitors or modulators of carnitinepalmitoyl transferase enzymes, inhibitors of fructose 1,6-diphosphatase,inhibitors of aldose reductase, mineralocorticoid receptor inhibitors,inhibitors of TORC2, inhibitors of CCR2 and/or CCR5, inhibitors of PKCisoforms (e.g., PKCa, PKCb, PKCg), inhibitors of fatty acid synthetase,inhibitors of serine palmitoyl transferase, modulators of GPR81, GPR39,GPR43, GPR41, GPR105, Kv1.3, retinol binding protein 4, glucocorticoidreceptor, somatostain receptors (e.g., SSTR1, SSTR2, SSTR3 and SSTR5),inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4,modulators of IL1 family including ILlbeta, and modulators of RXRalpha.In addition, suitable anti-diabetic agents include mechanisms listed byCarpino, P. A., Goodwin, B. Expert Opin. Ther. Pat, 2010, 20(12),1627-51;

(iii) anti-hyperglycemic agents, for example, those described at page31, line 31 through page 32, line 18 of WO 2011005611;

(iv) lipid lowering agents (for example, those described at page 30,line 20 through page 31, line 30 of WO 2011005611), andanti-hypertensive agents (for example, those described at page 31, line31 through page 32, line 18 of WO 2011005611);

(v) acetylcholinesterase inhibitors, such as donepezil hydrochloride(ARICEPT®, MEMAC), physostigmine salicylate (ANTILIRIUM®), physostigminesulfate (ESERINE), ganstigmine, rivastigmine (EXELON®), ladostigil,NP-0361, galantamine hydrobromide (RAZADYNE®, REMINYL®, NIVALIN®),tacrine (COGNEX®), tolserine, memoquin, huperzine A (HUP-A;Neuro-Hitech), phenserine, bisnorcymserine (also known as BNC), andINM-176;

(vi) amyloid-β (or fragments thereof), such as Aβ₁₋₁₅ conjugated to panHLA DR-binding epitope (PADRE®), ACC-001 (Elan/Wyeth), and Affitope;

(vii) antibodies to amyloid-β (or fragments thereof), such as ponezumab,solanezumab, bapineuzumab (also known as AAB-001), AAB-002 (Wyeth/Elan),Gantenerumab, intravenous Ig (GAMMAGARD®), LY2062430 (humanized m266;Lilly), and those disclosed in International Patent Publication Nos.WO04/032868, WO05/025616, WO06/036291, WO06/069081, WO06/118959, in USPatent Publication Nos. US2003/0073655, US2004/0192898, US2005/0048049,US2005/0019328, in European Patent Publication Nos. EP0994728 and1257584, and in U.S. Pat. No. 5,750,349;

(viii) amyloid-lowering or -inhibiting agents (including those thatreduce amyloid production, accumulation and fibrillization) such aseprodisate, celecoxib, lovastatin, anapsos, colostrinin, pioglitazone,clioquinol (also known as PBT1), PBT2 (Prana Biotechnology),flurbiprofen (ANSAID®, FROBEN®) and its R-enantiomer tarenflurbil(FLURIZAN®), nitroflurbiprofen, fenoprofen (FENOPRON, NALFON®),ibuprofen (ADVIL®, MOTRIN®, NUROFEN®), ibuprofen lysinate, meclofenamicacid, meclofenamate sodium (MECLOMEN®), indomethacin (INDOCIN®),diclofenac sodium (VOLTAREN®), diclofenac potassium, sulindac(CLINORIL®), sulindac sulfide, diflunisal (DOLOBID®), naproxen(NAPROSYN®), naproxen sodium (ANAPROX®, ALEVE®), insulin-degradingenzyme (also known as insulysin), the gingko biloba extract EGb-761(ROKAN®, TEBONIN®), tramiprosate (CEREBRIL®, ALZHEMED®), KIACTA®),neprilysin (also known as neutral endopeptidase (NEP)), scyllo-inositol(also known as scyllitol), atorvastatin (LIPITOR®), simvastatin(ZOCOR®), ibutamoren mesylate, BACE inhibitors such as LY450139 (Lilly),BMS-782450, GSK-188909; gamma secretase modulators and inhibitors suchas ELND-007, BMS-708163 (Avagacestat), and DSP8658 (Dainippon); and RAGE(receptor for advanced glycation end-products) inhibitors, such asTTP488 (Transtech) and TTP4000 (Transtech), and those disclosed in U.S.Pat. No. 7,285,293, including PTI-777;

(ix) alpha-adrenergic receptor agonists, and beta-adrenergic receptorblocking agents (beta blockers); anticholinergics; anticonvulsants;antipsychotics; calcium channel blockers; catechol O-methyltransferase(COMT) inhibitors; central nervous system stimulants; corticosteroids;dopamine receptor agonists and antagonists; dopamine reuptakeinhibitors; gamma-aminobutyric acid (GABA) receptor agonists;immunosuppressants; interferons; muscarinic receptor agonists;neuroprotective drugs; nicotinic receptor agonists; norepinephrine(noradrenaline) reuptake inhibitors; quinolines; and trophic factors;

(x) histamine 3 (H3) antagonists, such as PF-3654746 and those disclosedin US Patent Publication Nos. US2005-0043354, US2005-0267095,US2005-0256135, US2008-0096955, US2007-1079175, and US2008-0176925;International Patent Publication Nos. WO2006/136924, WO2007/063385,WO2007/069053, WO2007/088450, WO2007/099423, WO2007/105053,WO2007/138431, and WO2007/088462; and U.S. Pat. No. 7,115,600);

(xi) N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine(NAMENDA, AXURA, EBIXA), amantadine (SYMMETREL), acamprosate (CAMPRAL),besonprodil, ketamine (KETALAR), delucemine, dexanabinol, dexefaroxan,dextromethorphan, dextrorphan, traxoprodil, CP-283097, himantane,idantadol, ipenoxazone, L-701252 (Merck), lancicemine, levorphanol(DROMORAN), methadone (DOLOPHINE), neramexane, perzinfotel,phencyclidine, tianeptine (STABLON), dizocilpine (also known as MK-801),ibogaine, voacangine, tiletamine, riluzole (RILUTEK), aptiganel(CERESTAT), gavestinel, and remacimide;

(xii) monoamine oxidase (MAO) inhibitors, such as selegiline (EMSAM),selegiline hydrochloride (1-deprenyl, ELDEPRYL, ZELAPAR),dimethylselegiline, brofaromine, phenelzine (NARDIL), tranylcypromine(PARNATE), moclobemide (AURORIX, MANERIX), befloxatone, safinamide,isocarboxazid (MARPLAN), nialamide (NIAMID), rasagiline (AZILECT),iproniazide (MARSILID, IPROZID, IPRONID), iproclozide, toloxatone(HUMORYL, PERENUM), bifemelane, desoxypeganine, harmine (also known astelepathine or banasterine), harmaline, linezolid (ZYVOX, ZYVOXID), andpargyline (EUDATIN, SUPIRDYL);

(xiii) phosphodiesterase (PDE) inhibitors, including (a) PDE1 inhibitors(b) PDE2 inhibitors (c) PDE3 inhibitors (d) PDE4 inhibitors (e) PDE5inhibitors (f) PDE9 inhibitors (e.g., PF-04447943, BAY 73-6691 (BayerAG) and those disclosed in US Patent Publication Nos. US2003/0195205,US2004/0220186, US2006/0111372, US2006/0106035, and U.S. Ser. No.12/118,062 (filed May 9, 2008)), and (g) PDE10 inhibitors such as2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenoxy}methyl)quinoline(PF-2545920);

(xiv) serotonin (5-hydroxytryptamine) 1A (5-HT₄) receptor antagonists,such as spiperone, levo-pindolol, lecozotan;

(xv) serotonin (5-hydroxytryptamine) 2C (5-HT_(2c)) receptor agonists,such as vabicaserin, and zicronapine; serotonin (5-hydroxytryptamine) 4(5-HT₄) receptor agonists/antagonists, such as PRX-03140 (Epix) andPF-04995274;

(xvi) serotonin (5-hydroxytryptamine) 3C (5-HT_(3c)) receptorantagonists, such as Ondansetron (Zofran);

(xvii) serotonin (5-hydroxytryptamine) 6 (5-HT₆) receptor antagonists,such as mianserin (TOLVON, BOLVIDON, NORVAL), methiothepin (also knownas metitepine), ritanserin, SB-271046, SB-742457 (GlaxoSmithKline), LuAE58054 (Lundbeck A/S), SAM-760, and PRX-07034 (Epix);

(xviii) serotonin (5-HT) reuptake inhibitors such as alaproclate,citalopram (CELEXA, CIPRAMIL), escitalopram (LEXAPRO, CIPRALEX),clomipramine (ANAFRANIL), duloxetine (CYMBALTA), femoxetine (MALEXIL),fenfluramine (PONDIMIN), norfenfluramine, fluoxetine (PROZAC),fluvoxamine (LUVOX), indalpine, milnacipran (IXEL), paroxetine (PAXIL,SEROXAT), sertraline (ZOLOFT, LUSTRAL), trazodone (DESYREL, MOLIPAXIN),venlafaxine (EFFEXOR), zimelidine (NORMUD, ZELMID), bicifadine,desvenlafaxine (PRISTIQ), brasofensine, vilazodone, cariprazine andtesofensine;

(xix) Glycine transporter-1 inhibitors such as paliflutine, ORG-25935,and ORG-26041; and mGluR modulators such as AFQ-059 and amantidine;

(xx) AMPA-type glutamate receptor modulators such as perampanel,mibampator, selurampanel, GSK-729327, andN-{(3S,4S)-4-[4-(5-cyanothiophen-2-yl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide;

(xxi) P450 inhibitors, such as ritonavir;

(xxii) tau therapy targets, such as davunetide;

and the like.

The present invention further comprises kits that are suitable for usein performing the methods of treatment described above. In oneembodiment, the kit contains a first dosage form comprising one or moreof the compounds of the present invention and a container for thedosage, in quantities sufficient to carry out the methods of the presentinvention.

In another embodiment, the kit of the present invention comprises one ormore compounds of the invention.

General Synthetic Schemes

The compounds of Formula I may be prepared by the methods describedbelow, together with synthetic methods known in the art of organicchemistry, or modifications and transformations that are familiar tothose of ordinary skill in the art. The starting materials used hereinare commercially available or may be prepared by routine methods knownin the art [such as those methods disclosed in standard reference bookssuch as the Compendium of Organic Synthetic Methods, Vol. I-XII(published by Wiley-lnterscience)]. Preferred methods include, but arenot limited to, those described below.

During any of the following synthetic sequences it may be necessaryand/or desirable to protect sensitive or reactive groups on any of themolecules concerned. This can be achieved by means of conventionalprotecting groups, such as those described in T. W. Greene, ProtectiveGroups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene andP. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley &Sons, 1991; and T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Chemistry, John Wiley & Sons, 1999, which are herebyincorporated by reference.

Compounds of Formula I, or their pharmaceutically acceptable salts, canbe prepared according to the reaction Schemes discussed herein below.Unless otherwise indicated, the substituents in the Schemes are definedas above. Isolation and purification of the products is accomplished bystandard procedures, which are known to a chemist of ordinary skill.

It will be understood by one skilled in the art that the varioussymbols, superscripts and subscripts used in the schemes, methods andexamples are used for convenience of representation and/or to reflectthe order in which they are introduced in the schemes, and are notintended to necessarily correspond to the symbols, superscripts orsubscripts in the appended claims. Additionally, one skilled in the artwill recognize that in many cases, these compounds will be mixtures andenantiomers that may be separated at various stages of the syntheticschemes using conventional techniques, such as, but not limited to,crystallization, normal-phase chromatography, reversed phasechromatography and chiral chromatography, to afford single enantiomers.The schemes are representative of methods useful in synthesizing thecompounds of the present invention. They are not to constrain the scopeof the invention in any way.

Scheme 1 refers to the preparation of compounds of Formula I. Referringto Scheme 1, the compound of Formula I can be prepared from the compoundof Formula II through removal of protecting group P¹. P¹ in this caserefers to groups well known to those skilled in the art for amineprotection. For example, P¹ may be a benzoyl group (Bz), which can becleaved via acidic conditions, or through treatment with1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in methanol. Alternatively P¹may be one of many other protecting group suitable for amines, including9-fluorenylmethoxycarbonyl (Fmoc) or tert-butoxycarbonyl (BOC) and canbe cleaved under standard conditions known to one skilled in the art.

Scheme 2 refers to the preparation of compounds II wherein P¹ is Bz orBoc and R³ is CN. Protected thiazin-2-amines of Formula III aresubjected to standard palladium-catalyzed cyanation conditions (as in J.Med. Chem. 2005, 48, 1132-1144), for example, zinc cyanide andbis-palladium trisdibenzylideneacetone, to give compounds of Formula II.Compound II can be converted into a compound of Formula I according tothe methods of Scheme 1.

Scheme 3 refers to the preparation of compounds III wherein P¹ is Bz orBoc. The oxidation of compounds of Formula IV to carboxylic acids V canbe accomplished by a number of standard oxidation protocols, forinstance using tetrapropylammonium perruthenate (TPAP) andN-methylmorpholine-N-oxide (NMO) in acetonitrile. Carboxylic acid V canbe converted to compounds of Formula III via a number of methodsoutlined in the following reference: Practical Synthetic OrganicChemistry: Reactions, Principles, and Techniques. 2011, Chapter 13,Wiley & Sons, Inc., Caron, S., ed., as well as additional methods knownto those skilled in the art. A compound of Formula III can be convertedinto a compound of Formula I according to the methods of Schemes 2, 7and 1.

Scheme 4 refers to the preparation of compounds III wherein P¹ is Bz orBoc. The oxidation of compounds of Formula IV to aldehydes VI can beeffected by a number of standard oxidation protocols, for instance usingDess-Martin periodinane or sulfur trioxide-pyridine with DMSO(Parikh-Doering conditions). Aldehyde VI can be converted to compoundsof Formula III via a number of methods outlined in the followingreference: Practical Synthetic Organic Chemistry: Reactions, Principles,and Techniques. 2011, Chapter 13, Wiley & Sons, Inc., Caron, S., ed.Compound III can be converted into a compound of Formula I according tothe methods of Schemes 2, 7 and 1.

Scheme 5 refers to the preparation of compounds III wherein P¹ is Bz orFmoc. Isoxazolidines of Formula VII are subjected to reducingconditions, for instance zinc in acetic acid, affording compounds ofFormula VIII. These amino alcohols are treated with an isothiocyanate,for instance benzoyl isothiocyanate, to provide thioureas of Formula IX.Cyclization is induced using 1-chloro-N,N,2-trimethylpropenylamine(Ghosez' reagent), or alternatively trifluoroacetic anhydride orstandard Mitsunobu conditions, to give compounds of Formula III.Compound III can be converted into a compound of Formula I according tothe methods of Schemes 2, 7 and 1.

Scheme 6 refers to the preparation of compounds III wherein R² is CH₂F.Primary alcohols of Formula IV (which may be obtained via the chemistrydepicted in Scheme 8) are treated with an appropriate fluorinatingreagent, for instance diethylaminosulfur trifluoride (DAST), althoughother suitable fluorinating reagents known to one skilled in the art canbe utilized. The resulting compounds of Formula III can be convertedinto compounds of Formula I according to the methods of Schemes 2, 7 and1.

Scheme 7 refers to the preparation of compounds II wherein R³ is—CH₂NH-alkyl. Nitriles of Formula X (which may be obtained via thechemistry depicted in Scheme 2) are subjected to reduction conditions inthe presence of an electrophilic protecting group reagent, for instancesodium borohydride in the presence of nickel chloride and di-tert-butyldicarbonate (Boc₂O), although other suitable reducing reagents orprotecting groups known to one skilled in the art can be utilized. Theamines of Formula XI are then deprotected under suitable conditions, forinstance hydrochloric acid in dioxane, although other methods forremoving the tert-butoxycarbonyl (Boc) group can also be used. Theresulting compounds of Formula XII are then treated with an appropriatealkylating agent, for instance trifluoroethyl trifluoromethanesulfonate,to provide compounds of Formula II wherein R³ is —CH₂NH-alkyl, which canbe converted into compounds of Formula I according to the methods ofScheme 1.

Scheme 8 refers to the preparation of compounds IV wherein P¹ is Bz orFmoc. Isoxazolidines of Formula XIII (which may be obtained via thechemistry depicted in Scheme 9, utilizing a benzyloxymethyl group inplace of R²) are subjected to reducing conditions, for instance zinc inacetic acid, affording compounds of Formula XIV. The amino alcohols XIVare treated with an isothiocyanate, for instance benzoyl isothiocyanate,to provide thioureas of Formula XV. Cyclization is induced using Ghosez'reagent or strong acid, including for instance sulfuric acid;alternatively, standard Mitsunobu conditions can be employed, to givecompounds of Formula XVI. Cleavage of the benzyl ether under standardconditions, for instance using boron trichloride, provides alcohols ofFormula IV. Compound IV can be converted into a compound of Formula Iaccording to the methods of Schemes 2-4, 6, 7 and 1.

Scheme 9 refers to the preparation of compound VII. Homoallylic alcoholXVII is alkylated with 2-bromo-1,1-dimethoxyethane under basicconditions, such as treatment with potassium hydride, to provide thecorresponding ether XVIII. The acetal is cleaved under acidicconditions, aqueous hydrochloric acid as an example, to give aldehydeXIX. Condensation with a hydroxylamine salt, such as hydroxylaminesulfate, provides a geometric mixture of the corresponding oxime XX.Cycloaddition to form isoxazoline XXI may be carried out by treatment ofoxime XX with an oxidizing agent, such as sodium hypochlorite orN-chlorosuccinimide. Reaction of isoxazoline XXI with an appropriatearylmetallic reagent [for instance, an aryllithium such as(5-bromo-2,4-difluorophenyl)lithium or (5-bromo-2-fluorophenyl)lithium,or the corresponding aryl Grignard reagents] at low temperature, e.g.,−78° C., yields compounds of Formula VII. One of ordinary skill in theart will recognize that the stereochemistry of addition of thearylmetallic reagent is determined by the stereochemistry of theadjacent methine center, yielding a racemic mixture of cis-fuseddiastereomers, which can be converted into compounds of Formula Iaccording to the methods of Schemes 5, 2, 7 and 1.

Scheme 10 refers to the preparation of compounds II wherein P¹ is Bz orFmoc. Reaction of isoxazoline XXI with an appropriate arylmetallicreagent (for instance, an aryllithium such as2-fluoro-5-cyanophenyllithium, or the corresponding aryl Grignardreagent) at low temperature, e.g., −78° C., yields compounds of FormulaXXII. Isoxazolidines of Formula XXII are subjected to reducingconditions, for instance zinc in acetic acid, affording compounds ofFormula XXIII. These amino alcohols are treated with an isothiocyanate,for instance benzoyl isothiocyanate, to provide thioureas of FormulaXXIV. Cyclization is induced using 1-chloro-N,N,2-trimethylpropenylamine(Ghosez' reagent) to give compounds of Formula II. Compound II can beconverted into a compound of Formula I according to the methods ofScheme 1.

Scheme 11 refers to the preparation of secondary alcohols of FormulaXXV. Reaction of (R)-2-[(benzyloxy)methyl]oxirane with an appropriatealkenylmetallic reagent (for instance, an alkenyl Grignard such aspropenylmagnesium bromide), in the presence of copper iodide, yieldscompounds of Formula XXV. Compound XXV can be converted into a compoundof Formula I according to the methods of Scheme 9, 5, 2 and 1.

Scheme 12 refers to an alternative preparation of compounds II.Treatment of aryl bromide III under palladium-catalyzed carbonylationconditions, such as catalytic[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in methanolunder an atmosphere of carbon monoxide, affords the corresponding methylester XXVI. Subsequent reduction using an appropriate hydride source,including but not limited to lithium aluminum hydride, yields compoundsof Formula XXVII. Oxidation of the primary alcohols using an appropriateoxidant, including but not limited to pyridinium chlorochromate (PCC),affords the corresponding aldehyde of Formula XXVIII. Treatment of thealdehyde with the desired amine, such as 1-methoxypropane-2-amine, and areductant suitable for reductive amination conditions, such as sodiumborohydride or sodium triacetoxyborohydride, provides compounds ofFormula II. Compound II can be converted into a compound of Formula Iaccording to the methods of Scheme 1.

Scheme 13 describes an alternative preparation of compounds of FormulaXXVIII. Treatment of aryl bromide III under lithium-halogen exchangeconditions using an alkyllithium, such as methyllithium orsec-butyllithium, and subsequent trapping with an aldehyde equivalent,including but not limited to N-methyl-N-phenylformamide, providescompounds of Formula XXVIII. Compound XXVIII can be converted into acompound of Formula I according to the methods of Schemes 12 and 1.

Scheme 14 describes an alternative preparation of compounds of FormulaXVIIIb, where the stereochemistry of the double bond is of the Econfiguration. Treatment of secondary alcohol XXIX (prepared by themethods described by G. V. M. Sharma and K. Veera Babu, Tetrahedron:Asymmetry 2007, 18, 2175-2184) with 1,1-diethoxy-2-iodoethane using abase, such as sodium hydride, provides compounds of Formula XXX.Deprotection of compound XXX, for instance when P² is2-tetrahydropyranyl, with benzenesulfonic acid, provides propargylalcohols of Formula XXXI. Reduction using a stereospecific reducingagent, including but not limited to lithium aluminum hydride, providesallylic alcohols of Formula XVIIIb. Compounds of Formula XVIIIb can beconverted into a compound of Formula I according to the methods ofSchemes 9, 5, 2 and 1.

Preparation P1(3aR,5R)-5-[(Benzyloxy)methyl]-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole(P1)

Step 1. Synthesis of (2R)-1-(benzyloxy)pent-4-en-2-ol (C1)

To a solution of (2R)-2-[(benzyloxy)methyl]oxirane (167 g, 1.02 mol) intetrahydrofuran (2 L) was added copper(I) iodide (11.62 g, 61.02 mmol)at room temperature. The mixture was stirred for 5 minutes, then cooledto −78° C. A solution of vinylmagnesium bromide (1 M in tetrahydrofuran,1.12 L, 1.12 mol) was added drop-wise over 1 hour while the reactiontemperature was maintained below −70° C. Upon completion of theaddition, the cooling bath was removed and the reaction mixture was leftto stir at room temperature for 1 hour, then quenched by slow additionof aqueous ammonium chloride solution (200 mL). After dilution withadditional aqueous ammonium chloride solution (1.5 L) and ethyl acetate(1.5 L), the aqueous layer was extracted with ethyl acetate (1 L) andthe combined organic layers were washed with aqueous ammonium chloridesolution (1.5 L), dried over magnesium sulfate, filtered, andconcentrated in vacuo. Three batches of this reaction were carried outand combined to give the product as an orange oil. Yield: 600 g, 3.1mmol, quantitative. ¹H NMR (400 MHz, CDCl₃) δ 7.28-7.40 (m, 5H),5.78-5.90 (m, 1H), 5.08-5.17 (m, 2H), 4.57 (s, 2H), 3.86-3.94 (m, 1H),3.53 (dd, J=9.6, 3.3 Hz, 1H), 3.39 (dd, J=9.6, 7.4 Hz, 1H), 2.26-2.34(m, 3H).

Step 2. Synthesis of({[(2R)-2-(2,2-diethoxyethoxyl)pent-4-en-1-yl]oxy}methyl)benzene (C2)

To a suspension of sodium hydride (60% in mineral oil, 98.8 g, 2.47 mol)in tetrahydrofuran (1 L) at room temperature was added drop-wise over 30minutes a solution of (2R)-1-(benzyloxy)pent-4-en-2-ol (C1) (190 g,0.988 mol) in tetrahydrofuran (500 mL), while the reaction temperaturewas maintained below 30° C. After 30 minutes, a solution of2-bromo-1,1-diethoxyethane (390 g, 1.98 mol) in tetrahydrofuran (500 mL)was added drop-wise. The reaction mixture was stirred at roomtemperature for 1 hour, then the temperature was gradually increased to70° C. and the reaction mixture was left to stir at 70° C. for 18 hours.It was then cooled to room temperature, subsequently cooled in an icebath, and quenched by slow addition of ice/water (200 mL), while keepingthe internal reaction temperature at approximately 18° C. The mixturewas partitioned between saturated aqueous sodium chloride solution (1 L)and ethyl acetate (1 L), and the organic layer was washed with saturatedaqueous sodium chloride solution (1 L), dried over magnesium sulfate,filtered, and concentrated under reduced pressure. Purification waseffected by filtration through a pad of silica (Gradient: 0% to 20%ethyl acetate in heptane) to afford the product as an orange oil. Yield:257 g of 60% purity, approximately 500 mmol, 51% yield and 57.76 g of90% purity, approximately 170 mmol, 17% yield. ¹H NMR (400 MHz, CDCl₃),product peaks only: δ 7.26-7.38 (m, 5H), 5.78-5.90 (m, 1H), 5.02-5.13(m, 2H), 4.61 (t, J=5.3 Hz, 1H), 4.55 (s, 2H), 3.48-3.74 (m, 9H),2.31-2.37 (m, 2H), 1.22 (t, J=7.1 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H).

Step 3. Synthesis of2-{[(2R)-1-(benzyloxy)pent-4-en-2-yl]oxy}-N-hydroxyethanimine (C3)

A solution of({[(2R)-2-(2,2-diethoxyethoxyl)pent-4-en-1-yl]oxy}methyl)benzene (C2)(234 g, 0.759 mol) in formic acid (400 mL) and water (100 mL) wasstirred at room temperature for 2 hours. As LCMS analysis revealed asmall amount of remaining starting material, formic acid (50 mL) wasadded and the reaction mixture was stirred for a further 30 minutes. Thereaction mixture was diluted with ethanol (1 L) and water (400 mL).Hydroxylamine sulfate (435 g, 2.65 mol) and sodium acetate (217 g, 2.64mol) were added and the reaction was stirred at room temperature for 18hours. The reaction mixture was then filtered and concentrated in vacuo;the residue was partitioned between ethyl acetate (500 mL) and water (1L), and the aqueous layer was extracted with ethyl acetate (3×500 mL).The combined organic layers were washed with saturated aqueous sodiumchloride solution (2×500 mL), dried over magnesium sulfate, filtered,and concentrated under reduced pressure to provide the product as anorange oil (234 g), which was taken directly to the following step. By¹H NMR, this material consisted of a roughly 1:1 mixture of oximeisomers. LCMS m/z 250.1 [M+H⁺]. ¹H NMR (400 MHz, CDCl₃), characteristicpeaks: δ [7.52 (t, J=5.5 Hz) and 6.96 (t, J=3.6 Hz), total 1H],7.28-7.39 (m, 5H), 5.74-5.87 (m, 1H), 5.04-5.14 (m, 2H), 4.55 and 4.56(2 s, total 2H), {4.45-4.55 (m) and [4.27 (dd, half of ABX pattern,J=13.2, 5.4 Hz) and 4.21 (dd, half of ABX pattern, J=13.2, 5.6 Hz)],total 2H}, 2.30-2.37 (m, 2H).

Step 4. Synthesis of(3aR,5R)-5-[(benzyloxy)methyl]-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole(P1)

An aqueous solution of sodium hypochlorite (14.5% solution, 600 mL) wasadded drop-wise to a 0° C. solution of2-{[(2R)-1-(benzyloxy)pent-4-en-2-yl]oxy}-N-hydroxyethanimine (C3) (224g from the previous step, <0.759 mol) in dichloromethane (1 L), whilethe internal temperature was maintained below 15° C. After completion ofthe addition, the reaction mixture was left to stir at 0° C. for 1.5hours, then diluted with water (1 L) and dichloromethane (500 mL). Theaqueous layer was extracted with dichloromethane (2 10×500 mL), and thecombined organic layers were washed with saturated aqueous sodiumchloride solution (500 mL), water (500 mL) and again with saturatedaqueous sodium chloride solution (500 mL). They were subsequently driedover magnesium sulfate, filtered, and concentrated in vacuo.Purification via silica gel chromatography (Gradient: 0% to 25% ethylacetate in heptane) afforded the product as a colorless oil. Theindicated relative stereochemistry of compound P1 was assigned based onnuclear Overhauser enhancement studies, which revealed an interactionbetween the methine protons on carbons 3a and 5. Yield: 85.3 g, 345mmol, 45% over 2 steps. LCMS m/z 248.1 [M+H⁺]. ¹H NMR (400 MHz, CDCl₃) δ7.27-7.40 (m, 5H), 4.77 (d, J=13.5 Hz, 1H), 4.54-4.65 (m, 3H), 4.22 (dd,J=13.5, 1 Hz, 1H), 3.79 (dd, J=11.7, 8.0 Hz, 1H), 3.69-3.76 (m, 1H),3.57 (dd, half of ABX pattern, J=10.1, 5.9 Hz, 1H), 3.49 (dd, half ofABX pattern, J=10.1, 4.3 Hz, 1H), 3.39-3.5 (m, 1H), 2.20 (ddd, J=12.9,6.5, 1.6 Hz, 1H), 1.51-1.62 (m, 1H).

Alternate conversion of({[(2R)-2-(2,2-diethoxyethoxyl)pent-4-en-1-yl]oxy}methyl)benzene (C2) to(3aR,5R)-5-[(benzyloxy)methyl]-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole(P1)

Step 1. Synthesis of2-{[(2R)-1-(benzyloxy)pent-4-en-2-yl]oxy}-N-hydroxyethanimine (C3)

({[(2R)-2-(2,2-Diethoxyethoxyl)pent-4-en-1-yl]oxy}methyl)benzene (C2)(12.4 g, 40.2 mmol) was dissolved in acetic acid (28 mL) and water (12mL). Hydroxylamine hydrochloride (2.84 g, 40.9 mmol) was added as asolid. After 1 hour, additional hydroxylamine hydrochloride (2.84 g,40.9 mmol) was added. After 1 more hour, the reaction mixture wasdiluted with tert-butyl methyl ether (100 mL) and washed with water(3×50 mL), then washed with aqueous potassium carbonate solution (0.5 M,100 mL). The organic layer was concentrated to provide the product as apale yellow oil, which consisted of a roughly equimolar mixture of oximeisomers, as assessed by ¹H NMR. Yield: 9.60 g, 38.5 mmol, 96%. ¹H NMR(400 MHz, CDCl₃) δ 7.98 and 7.67 (2 br s, total 1H), [7.50 (t, J=5.6 Hz)and 6.95 (t, J=3.6 Hz), total 1H], 7.28-7.39 (m, 5H), 5.74-5.87 (m, 1H),5.04-5.14 (m, 2H), 4.55 and 4.56 (2 s, total 2H), 4.47-4.49 (m, 1H),4.18-4.28 (m, 1H), 3.47-3.65 (m, 3H), 2.30-2.37 (m, 2H).

Step 2. Synthesis of(3aR,5R)-5-[(benzyloxy)methyl]-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole(P1)

Pyridine (23.1 mL, 286 mmol) was added to a solution of2-{[(2R)-1-(benzyloxy)pent-4-en-2-yl]oxy}-N-hydroxyethanimine (C3) (35.6g, 143 mmol) in dichloromethane (350 mL). N-Chlorosuccinimide (19.4 g,145 mmol) was added in portions over roughly 2 hours. The reaction wasstirred for 3 hours, then diluted with an aqueous solution of sodiumsulfite (5 g in 100 mL water). The mixture was stirred for 20 minutes,and the aqueous layer was extracted with dichloromethane; the combinedorganic layers were washed with water, dried, and concentrated.Purification via silica gel chromatography (Eluent: 1:2 ethylacetate/hexanes) afforded the product. Yield: 21.2 g, 85.7 mmol, 60%. ¹HNMR (400 MHz, CDCl₃) δ 7.28-7.40 (m, 5H), 4.77 (d, J=13.4 Hz, 1H),4.55-4.65 (m, 3H), 4.22 (dd, J=13.5, 1.3 Hz, 1H), 3.79 (dd, J=11.7, 8.0Hz, 1H), 3.69-3.76 (m, 1H), 3.57 (dd, half of ABX pattern, J=10.2, 5.9Hz, 1H), 3.49 (dd, half of ABX pattern, J=10.2, 4.3 Hz, 1H), 3.40-3.5(m, 1H), 2.21 (ddd, J=12.9, 6.5, 1.8 Hz, 1H), 1.57 (ddd, J=13, 12, 11Hz, 1H).

Preparation P2(3aR,5S)-5-Methyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole

Step 1: Synthesis of (4S)-4-(2,2-dimethoxyethoxyl)pent-1-ene (C4)

To a suspension of sodium hydride (60% in mineral oil, 13.9 g, 0.348mol) in tetrahydrofuran (350 mL) was added a solution of(S)-pent-4-en-2-ol (10.0 g, 0.116 mol) in tetrahydrofuran (50 mL) at 0°C. The reaction was warmed to room temperature and stirred for 30minutes and 2-bromo-1,1-diethoxyethane (68.6 g, 0.348 mol) was added atthe same temperature. The reaction mixture was refluxed for 18 hours.The mixture was cooled to 0° C. and quenched with water (50 mL). Themixture was partitioned between ethyl acetate (300 mL) and water (200mL). The organic phase was washed with brine (2×100 mL), dried andconcentrated in vacuo. Silica gel chromatography (petroleum ether/ethylacetate=30:1) provided the product as a yellow oil. Yield: 17.3 g, 99.6mmol, 74%. ¹H NMR (400 MHz, CDCl₃), δ 5.76-5.85 (m, 1H), 5.02-5.09 (m,2H), 4.58-4.60 (m, 1H), 3.66-3.74 (m, 2H), 3.43-3.61 (m, 5H), 2.29-2.36(m, 1H), 2.13-2.20 (m, 1H), 1.21 (t, J=7.2 Hz, 6H), 1.14 (d, J=6.4 Hz,3H).

Step 2: Synthesis of (1E)-N-hydroxy-2-[(2S)-pent-4-en-2-yloxy]ethanimine(C5)

To a solution of C4 (17.4 g, 85.8 mmol) in tetrahydrofuran (100 mL) wasadded aqueous hydrochloric acid (2 M, 51.0 mL, 0.102 mol) at roomtemperature. The reaction was heated to 75° C. for 1 hour. The mixturewas concentrated in vacuo, at which point ethanol (100 mL) and water (20mL) were added, followed by the addition of sodium acetate (35.17 g,0.429 mol) and hydroxylamine hydrochloride (17.9 g, 0.257 mol). Thereaction was stirred at 60° C. for 18 hours. The reaction mixture wasconcentrated in vacuo and the residue was partitioned between water anddichloromethane. The aqueous layer was extracted with dichloromethane(3×200 mL). The combined organic phases were dried over sodium sulfate,filtered and concentrated in vacuo. Silica gel chromatography (petroleumether/ethyl acetate=10:1) provided the product as a yellow oil, whichwas used without further purification in the subsequent step. Yield: 8.6g, 60.1 mmol, 70%.

Step 3: Synthesis of(3aR,5S)-5-methyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (P2)

To a solution of C5 (8.6 g, 0.06 mol) and triethylamine (0.455 g, 4.50mmol) in dichloromethane (150 mL) at room temperature was slowly added a6% aqueous solution of sodium hypochlorite (90 mL) while maintaining theinternal temperature between 20° C. and 25° C. After the addition, theorganic phase was separated, dried and concentrated in vacuo. Silica gelchromatography (petroleum ether/ethyl acetate=10:1) provided the productas a yellow oil. Yield: 5.70 g, 40.4 mmol, 67%. LCMS m/z 142.1 [M+H⁺],¹H NMR (400 MHz, CDCl₃), δ 4.68 (d, J=13.2 Hz, 1H), 4.59 (dd, J=10, 8Hz, 1H), 4.18 (d, J=13.2 Hz, 1H), 3.76 (dd, J=12, 8 Hz, 1H), 3.59-3.66(m, 1H), 3.39-3.50 (m, 1H), 2.14-2.19 (m, 1H). 1.42-1.51 (m, 1H), 1.25(d, J=6 Hz, 3H).

Preparation P3(3S,3aR,5R)-5-[(Benzyloxy)methyl]-3-methyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole(P3)

Step 1. Synthesis of (2R)-1-(benzyloxy)hex-4-en-2-ol (C62)

The product was obtained according to the method used for synthesis ofC1 in Preparation P1, except that 1-propenylmagnesium bromide was usedin place of vinylmagnesium bromide. The product was obtained as a brownoil, which was used without further purification; by ¹H NMR, thismaterial consisted of a 1:1 mixture of geometric isomers. Yield: 140 g,0.679 mol, 100%. ¹H NMR (400 MHz, CDCl₃) δ 7.28-7.42 (m, 5H), 5.39-5.67(m, 2H), 4.57 (s, 2H), 3.80-3.92 (m, 1H), 3.48-3.57 (m, 1H), 3.35-3.43(m, 1H), 2.36-2.50 (br m, 1H), 2.24-2.33 (m, 1H), 2.17-2.24 (m, 1H),[1.68 (br d, J=6 Hz) and 1.64 (br d, J=7 Hz), total 3H].

Step 2. Synthesis of({[(2R)-2-(2,2-diethoxyethoxyl)hex-4-en-1-yl]oxy}methyl)benzene (C63)

Compound C62 (150 g, 0.73 mol) was converted to the product according tothe method used for synthesis of C2 in Preparation P1, except that theinitial combination of reagents was carried out at 0° C. The product wasobtained as a brown oil (400 g, <0.73 mol), which was used for the nextstep without further purification. By ¹H NMR analysis, this materialcontained a roughly 1:1 mixture of geometric isomers. ¹H NMR (400 MHz,CDCl₃), characteristic peaks for product: δ 7.25-7.38 (m, 5H), 5.38-5.60(m, 2H), 4.55 and 4.55 (2 s, total 2H), 2.22-2.37 (m, 2H), 1.60-1.68 (m,3H).

Step 3. Synthesis of {[(2R)-1-(benzyloxy)hex-4-en-2-yl]oxy}acetaldehyde(C64)

To a solution of C63 (350 g from the previous step, <0.64 mol) intetrahydrofuran (1.4 L) was added aqueous hydrochloric acid (2 M, 700mL), and the reaction mixture was stirred at 75° C. for 1 hour. Solventwas removed in vacuo and the aqueous residue was extracted with ethylacetate (2.0 L). The combined organic layers were washed with saturatedaqueous sodium chloride solution (3×500 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure. The product wasobtained as a pale brown oil (210 g, <0.64 mol), which was takendirectly to the following step.

Step 4. Synthesis of2-{[(2R)-1-(benzyloxy)hex-4-en-2-yl]oxy}-N-hydroxyethanimine (C65)

To a mixture of C64 (207 g, ≦0.63 mol) and sodium acetate (342 g, 4.17mol) in aqueous ethanol (2:1 ethanol/water, 2.1 L) was addedhydroxylamine hydrochloride (207 g, 2.98 mol). The reaction mixture wasstirred at 60° C. for 18 hours, then concentrated in vacuo and extractedwith ethyl acetate (2.0 L). The combined organic layers were dried oversodium sulfate, filtered, concentrated under reduced pressure, andpurified by chromatography on silica gel (Eluent: ethyl acetate inpetroleum ether) to afford the product as a brown oil. By ¹H NMR, thiswas assigned as a mixture of geometric isomers at both the oxime andolefin functional groups. Yield: 117 g, 0.444 mol, 70% over three steps.¹H NMR (400 MHz, CDCl₃), characteristic peaks: δ [7.42-7.48 (m) and6.88-6.92 (m), total 1H], 7.20-7.36 (m, 5H), 5.29-5.61 (m, 2H),[4.48-4.54 (m) and 4.41-4.45 (m), total 3H], 2.13-2.32 (m, 2H),1.54-1.65 (m, 3H).

Step 5. Synthesis of(3S,3aR,5R)-5-[(benzyloxy)methyl]-3-methyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole(P3) and(3R,3aR,5R)-5-[(benzyloxy)methyl]-3-methyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole(C66)

An aqueous solution of sodium hypochlorite (6.15% solution, 6.6 L) wasslowly added to a solution of C65 (660 g, 2.51 mol) and triethylamine(19 g, 0.19 mol) in dichloromethane (6.6 L) at 25° C. After completionof the addition, the reaction mixture was stirred at 25° C. for 30minutes. The organic layer was washed with water (3×3 L), dried oversodium sulfate, filtered, and concentrated in vacuo; purification viachromatography on silica gel (Eluent: ethyl acetate in petroleum ether)provided(3S,3aR,5R)-5-[(benzyloxy)methyl]-3-methyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole(P3) as a white solid. Yield: 90 g, 0.34 mol, 14%. The indicatedrelative stereochemistry of compound P3 was assigned based on nuclearOverhauser enhancement studies, which revealed interactions of themethine proton on carbon 3a with both the protons of the methyl group oncarbon 3 and the methine proton on carbon 5. LCMS m/z 261.9 [M+H⁺]. ¹HNMR (400 MHz, CDCl₃) δ 7.24-7.39 (m, 5H), 4.69 (d, J=13.7 Hz, 1H), 4.57(AB quartet, J_(AB)=12.2 Hz, Δν_(AB)=13.8 Hz, 2H), 4.13-4.25 (m, 2H),3.62-3.70 (m, 1H), 3.55 (dd, half of ABX pattern, J=10, 6 Hz, 1H), 3.47(dd, half of ABX pattern, J=10, 4 Hz, 1H), 2.93 (br ddd, J=11, 11, 7 Hz,1H), 2.11 (br dd, J=12.6, 6.8 Hz, 1H), 1.45-1.56 (m, 1H), 1.45 (d, J=6.2Hz, 3H).

Also obtained from the chromatographic separation was(3R,3aR,5R)-5-[(benzyloxy)methyl]-3-methyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole(C66), as a brown oil. Yield: 126 g, 0.482 mol, 19%. The indicatedrelative stereochemistry of compound C66 was assigned based on nuclearOverhauser enhancement studies, which revealed interactions of themethine proton on carbon 3a with both the methine proton on carbon 3 andthe methine proton on carbon 5. LCMS m/z 261.9 [M+H⁺]. ¹H NMR (400 MHz,CDCl₃) δ 7.26-7.39 (m, 5H), 4.76-4.86 (m, 1H), 4.75 (d, J=13.5 Hz, 1H),4.58 (AB quartet, J_(AB)=12.2 Hz, Δν_(AB)=12.4 Hz, 2H), 4.19 (dd,J=13.5, 1.2 Hz, 1H), 3.63-3.70 (m, 1H), 3.57 (dd, half of ABX pattern,J=10.2, 6.0 Hz, 1H), 3.49 (dd, half of ABX pattern, J=10.1, 4.2 Hz, 1H),3.36 (br ddd, J=11.4, 11.4, 6.3 Hz, 1H), 1.86 (ddd, J=12.8, 6.4, 1.2 Hz,1H), 1.55-1.66 (m, 1H), 1.16 (d, J=6.6 Hz, 3H).

Example 15-[(4aR,6R,8aS)-2-Amino-6-[(benzyloxy)methyl]-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluoro-2-methoxybenzonitrile(1)

Step 1: Synthesis of(3aR,5R,7aS)-5-[(benzyloxy)methyl]-7a-(5-bromo-2,4-difluorophenyl)hexahydro-1H-pyrano[3,4-c][1,2]oxazole(C6)

P1 (4.01 g, 16.5 mmol) was added to a three neck round-bottomed flask(oven dried) equipped with a thermocouple, a nitrogen inlet andmechanical overhead stirrer. Toluene:isopropyl ether (1:1, 160 mL) wasadded and the resulting solution was cooled to −74° C. Borontrifluoride-diethyl etherate (46.5%, 4.91 ml, 18.5 mmol) was added andthe resulting solution was allowed to stir at −74° C. for 30 minutes.2,4-Difluoro-1,5-di-bromobenzene (5.01 g, 18.4 mmol) was added followedby a slow addition of n-butyllithium (2.5 M in hexanes, 6.96 mL, 17.4mmol) ensuring the internal temperature did not rise >5° C. Theresulting solution was allowed to stir at −78° C. for 90 minutes.Saturated aqueous ammonium chloride (100 mL) was added and the resultingmixture was allowed to warm to room temperature, at which point it waspartitioned between ethyl acetate (1×200 mL) and water (1×600 mL). Theorganic layer was extracted and the aqueous was back extracted withethyl acetate (3×200 mL). The combined organics were washed with brine(1×100 mL) and the organic layer was dried over sodium sulfate,filtered, and the filtrate concentrated in vacuo. Silica gelchromatography (Gradient 10% to 70% ethyl acetate in heptane) providedthe product as a clear oily residue. Yield: 3.11 g, 7.06 mmol, 43%. ¹HNMR (400 MHz, CD₃OD), δ 8.09 (t, J=8.3 Hz, 1H), 7.31-7.36 (m, 4H),7.25-7.29 (m, 1H), 7.12 (dd, J=11.5, 8.4 Hz, 1H), 4.55 (s, 2H), 4.06(dd, J=12.6, 1.7 Hz, 1H), 3.78 (d, J=12.5 Hz, 1H), 3.73-3.8 (m, 1H),3.69 (d, J=7.2 Hz, 1H), 3.53-3.57 (m, 2H), 3.49 (dd, J=7.3, 5.2 Hz, 1H),3.05-3.11 (m, 1H), 1.82-1.87 (m, 1H), 1.52-1.61 (m, 1H).

Step 2: Synthesis of[(2R,4R,5S)-5-amino-2-((benzyloxy)methyl)-5-(5-bromo-2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]methanol(C7)

To C6 (1.0 g, 2.27 mmol) in tetrahydrofuran (1 mL) cooled to 0° C. wasadded a tetrahydrofuran solution of samarium iodide (0.1 M, 90.8 mL,9.08 mmol) in a drop-wise manner. The resulting solution was allowed tostir at room temperature for 90 minutes. A saturated aqueous solution ofsodium thiosulfate pentahydrate (1 L) was added to the reaction,followed by extraction with ethyl acetate (3×250 mL). The combinedorganics were washed with brine (1×500 mL), dried over sodium sulfate,filtered and concentrated in vacuo to afford a clear oily residue. Theresidue was dissolved in dichloromethane (5 mL) and filtered through asilica gel plug (approx 100 g) with dichloromethane (3×100 mL). Thecombined filtrates were concentrated in vacuo to afford the product as aclear oily residue, which was used directly in the next step. Yield: 947mg, 2.14 mmol, 94%. LCMS m/z 443.1 [M+H⁺], Br isotopic pattern. ¹H NMR(400 MHz, CD₃OD), characteristic peaks: δ 8.00 (t, J=8.1 Hz, 1H),7.24-7.38 (m, 5H), 7.10 (dd, J=12.1, 8.4 Hz, 1H), 4.58 (s, 2H), 4.03(dd, J=11.2, 2.2 Hz, 1H), 3.72-3.80 (m, 1H), 3.56-3.64 (m, 2H), 3.44 (d,J=11.3 Hz, 1H), 3.34, (d, J=5.1 Hz, 1H), 2.46-2.53 (m, 1H), 1.68-1.80(m, 2H).

Step 3: Synthesis ofN-[((3S,4R,6R)-6-((benzyloxy)methyl)-3-(5-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamothioyl]benzamide(C8)

To C7 (0.946 g, 2.14 mmol) in dichloromethane (22 mL) was added benzoylisothiocyanate (0.273 mL, 2.04 mmol) and the resulting solution wasallowed to stir at room temperature for 18 hours. The reaction mixturewas concentrated in vacuo, providing the product as an orange oilyresidue, which was carried forward into the next step without furtherpurification. Yield: 964 mg, 1.59 mmol, 74%. LCMS m/z 607.6 [M+H⁺], Brisotopic pattern. ¹H NMR (400 MHz, CD₃OD), characteristic peaks: δ7.89-7.90 (m, 2H), 7.62-7.66 (m, 2H), 7.50-7.54 (m, 2H), 7.31 (d, J=6.6Hz, 2H), 7.18-7.25 (m, 2H), 7.06 (dd, J=11.9, 8.8 Hz, 2H), 4.52-4.59 (m,2H), 3.84-3.90 (m, 3H), 3.55-3.64 (m, 3H), 3.45-4.51 (m, 1H) 1.90-1.99(m, 3H).

Step 4: Synthesis ofN-[(6R)-6-[(benzyloxy)methyl]-8a-(5-bromo-2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C9)

A solution of C8 (0.964 g, 1.59 mmol) and pyridine (0.487 ml, 6.05 mmol)in dichloromethane (27.0 mL) was cooled to −50° C. internal temperature.Trifluoromethanesulfonic anhydride (0.535 mL, 3.18 mmol) was addeddrop-wise to the solution and the mixture was gradually warmed to 0° C.and allowed to stir at that temperature for 3.5 hours. The reactionmixture was partitioned between dichloromethane (250 mL) and water (250mL). The organic layer was removed and washed with water (2×300 mL) andbrine (1×250 mL), then dried over magnesium sulfate, filtered andconcentrated in vacuo. Silica gel chromatography (Gradient 0% to 50%ethyl acetate in heptane) provided the product as a white solid. Yield:822 mg, 1.40 mmol, 88%. LCMS m/z 589.6 [M+H⁺], Br isotopic pattern. ¹HNMR (400 MHz, CD₃OD), characteristic peaks: δ 8.05-8.16 (m, 2H), 7.62(t, J=7.9 Hz, 1H), 7.61-7.67 (m, 1H), 7.42-7.49 (m, 2H), 7.28-7.33 (m,2H), 7.16-7.25 (m, 3H), 4.58 (d, J=11.7 Hz, 1H), 4.52 (d, J=11.7 Hz,1H), 4.07 (dd, J=11.9, 1.6 Hz, 1H), 3.89 (br d, J=11.9 Hz, 2H),3.54-3.62 (m, 2H), 3.11-3.18 (m, 1H), 2.96 (dd, J=13.2, 4.2 Hz, 1H),2.74 (dd, J=13.2, 2.8 Hz, 1H), 1.88-1.98 (m, 1H), 1.69 (d, J=11.7 Hz,1H).

Step 5: Synthesis ofN-[(6R)-6-[(benzyloxy)methyl]-8a-(5-cyano-2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C10)

C9 (300 mg, 0.511 mmol), zinc cyanide (72.0 mg, 0.613 mmol),tetrakis(triphenylphosphine)palladium(0) (342 mg, 0.296 mmol) andN,N-dimethylformamide (9 mL) were added to a 16 ml Emry microwave vial.The vial was sealed and purged with nitrogen for 10 minutes whilestirring. The reaction was heated at 80° C. in a Biotage microwave for120 minutes. The reaction mixture was partitioned between ethyl acetate(100 mL) and saturated aqueous sodium bicarbonate (200 mL). The organicwas separated and the aqueous layer was extracted with ethyl acetate(3×50 mL). The combined organics were washed with brine (1×200 mL),dried over sodium sulfate, filtered, and absorbed on silica gel. Theobtained solid after removal of solvent was subjected to silica gelchromatography (Gradient: 0% to 100% ethyl acetate in heptane) toprovide the desired product as a yellow solid. Yield: 269 mg, 0.503mmol, 98%. LCMS m/z 534.3 [M+H⁺].

Step 6: Synthesis of5-[(4aR,6R,8aS)-2-amino-6-[(benzyloxy)methyl]-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluoro-2-methoxybenzonitrile(1)

To a solution of C10 (30.0 mg, 0.056 mmol) in methanol (2 mL) was added1,8-diazabicycloundec-7-ene (6 μL, 0.039 mmol) and the resultingsolution was heated to reflux for 18 hours. The reaction mixture wascooled to room temperature and concentrated in vacuo. Silica gelchromatography (Gradient 0% to 20% methanol in dichloromethane) providedthe product as a yellow solid. Yield: 16.6 mg, 0.037 mmol, 66%. LCMS m/z442.2 [M+H⁺]. ¹H NMR (400 MHz, CD₃OD), δ 7.48 (d, J=8.6 Hz, 1H),7.29-7.35 (m, 4H), 7.24-7.27 (m, 1H), 7.02 (d, J=14.2 Hz, 1H), 4.57 (d,J=11.9 Hz, 1H), 4.53 (d, J=11.9 Hz, 1H), 4.02 (dd, J=11, 2.4 Hz, 1H),3.78-3.84 (m, 1H), 3.66 (d, J=11.1 Hz, 1H), 3.47-3.57 (m, 4H), 2.83-2.89(m, 2H), 2.65-2.69 (m, 1H), 1.73-1.82 (m, 1H), 1.50-1.55 (m, 1H),1.50-1.55 (m, 2H).

Example 25-[(4aR,6R,8aS)-2-Amino-6-[(benzyloxy)methyl]-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzonitrile(2)

Step 1: Synthesis of5-[(4aR,6R,8aS)-2-amino-6-[(benzyloxy)methyl]-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzonitrile(2)

To a solution of C10 (30.0 mg, 0.056 mmol) in absolute ethanol (0.5 mL)was added hydrazine monohydrate (0.030 mL, 0.392 mmol) and the resultingsolution was allowed to stir at room temperature for 45 minutes. Thereaction mixture was concentrated in vacuo. Silica gel chromatography(Gradient 0% to 10% methanol in dichloromethane) provided the desiredproduct as a yellow solid. Yield: 8.00 mg, 0.017 mmol, 30%. LCMS m/z430.2 [M+H⁺]. ¹H NMR (400 MHz, CD₃OD), characteristic peaks: δ 4.52-4.59(m, 2H), 4.02 (dd, J=11.4, 2.2 Hz, 1H), 3.82-3.86 (m, 1H), 3.72 (d,J=11.5 Hz, 1H), 2.76 (dd, J=12.8, 2.6 Hz, 1H), 1.75-1.83 (m, 1H),1.57-1.62 (m, 1H).

Example 35-[(4aR,6R,8aS)-2-Amino-6-(hydroxymethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzonitrile(3)

Step 1: Synthesis ofN-[(6R)-8a-(5-cyano-2,4-difluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C11)

To a solution of C10 (180 mg, 0.337 mmol) in dichloromethane (2 mL)cooled to −10° C. was added boron trichloride (1.52 mL, 1.52 mmol)drop-wise. The resulting solution was allowed to stir at −10° C. for 3hours. Methanol (15 mL) was added and the reaction was concentrated invacuo. Methanol (15 mL) was added to the residue and the solution wasconcentrated in vacuo. The process was then repeated. The residue wasflushed through a plug of silica gel with a 9:1 mixture ofdichloromethane/methanol (3×50 mL). The filtrates were combined andconcentrated in vacuo to provide the desired product as a yellow solid.Yield: 161 mg, 0.364 mmol, 108%. LCMS m/z 444.1 [M+H⁺]. ¹H NMR (400 MHz,CD₃OD), δ 8.07 (br s, 2H), 7.85 (t, J=6.8 Hz, 1H), 7.54-7.57 (m, 1H),7.45-7.49 (m, 2H), 7.38 (dd, J=12.1, 9.2 Hz, 1H), 4.06 (dd, J=11.4, 1.7Hz, 1H), 3.9 (d, J=11.9 Hz, 1H), 3.70-3.77 (m, 1H), 3.57 (d, J=5.3 Hz,2H), 3.09-3.17 (m, 1H), 2.96 (dd, J=12.9, 4.1 Hz, 1H), 2.75 (dd, J=13.2,2.8 Hz, 1H), 1.78-1.88 (m, 1H), 1.64-1.71 (m, 1H).

Step 2: Synthesis of5-[(4aR,6R,8aS)-2-amino-6-(hydroxymethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzonitrile(3)

N-[(6R)-8a-(5-Cyano-2,4-difluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C11) was converted to the product using the method described for thesynthesis of5-[(4aR,6R,8aS)-2-amino-6-[(benzyloxy)methyl]-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzonitrile(2) in Example 2. Yield: 14.2 mg, 0.042 mmol, 62%. LCMS m/z 340.1[M+H⁺]. ¹H NMR (400 MHz, CD₃OD), δ 7.64 (t, J=7.9 Hz, 1H), 7.30 (dd,J=12.1, 9.2 Hz, 1H), 4.02 (dd, J=11.1, 2.5 Hz, 1H), 3.64-3.70 (m, 2H),3.50-3.58 (m, 2H), 2.85-2.93 (m, 2H), 2.68-2.72 (m, 1H), 1.68-1.78 (m,1H), 1.50-1.55 (m, 1H).

Example 45-[(4aR,6R,8aS)-2-Amino-6-(fluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzonitrile(4)

Step 1: Synthesis ofN-[(4aR,6R,8aS)-8a-(5-bromo-2,4-difluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C12)

A solution of C9 (3.22 g, 5.48 mmol) in ethyl acetate (100 mL) wastreated with a solution of sodium bromate (4.14 g, 27.4 mmol) in water(66 mL). To the well stirred biphasic system was added a solution ofsodium dithionite (4.77 g, 27.4 mmol) in water (134 mL) drop-wise over30 minutes. The reaction mixture was stirred for 90 minutes and thendiluted with ethyl acetate (500 mL). The organic layer was removed andthe aqueous was extracted with ethyl acetate (3×100 mL). The combinedorganics were then washed with an aqueous solution of sodium thiosulfatepentahydrate (3×300 mL), brine (300 mL), and then dried over sodiumsulfate, filtered and concentrated in vacuo. Silica gel chromatography(Gradient: 0% to 100% ethyl acetate in heptane) provided the product asa white solid. Yield: 1.77 g, 3.57 mmol, 65%. LCMS m/z 499.1 [M+H⁺], Brisotopic pattern. ¹H NMR (400 MHz, CD₃OD), characteristic peaks: δ 8.11(d, J=6.5 Hz, 2H), 7.64 (t, J=7.9 Hz, 1H), 7.53-7.57 (m, 1H), 7.44-7.48(m, 2H), 7.24 (dd, J=12, 8.3 Hz, 1H), 4.09 (dd, J=11.6, 1.9 Hz, 1H), 3.9(d, J=11.9 Hz, 1H), 3.72-3.77 (m, 1H), 3.58 (d, J=5.1 Hz, 2H), 3.11-3.19(m, 1H), 2.97 (dd, J=13.3, 4.1 Hz, 1H), 2.75 (dd, J=13.1, 2.7 Hz, 1H),1.84 (q, J=11.6 Hz, 1H), 1.66-1.71 (m, 1H).

Step 2: Synthesis ofN-[(4aR,6R,8aS)-8a-(5-bromo-2,4-difluorophenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C13)

Diethylaminosulfur trifluoride (0.860 g, 5.34 mmol) was added to asolution of pentanes (70 mL) and dichloromethane (35 mL). To theresulting clear solution was added a solution of C12 (1.77 g, 3.56 mmol)in dichloromethane (71 mL) in a drop-wise manner and the mixture wasallowed to stir at room temperature for 16 hours. Aqueous saturatedsodium bicarbonate solution (200 mL) was added and the aqueous wasextracted with dichloromethane (3×200 mL). The combined organics werewashed with brine (200 mL), dried over magnesium sulfate, filtered andconcentrated. Silica gel chromatography (Gradient: 0% to 100% ethylacetate in heptane) provided 1.5 g of a white solid, which wastriturated with diethyl ether (20 mL) to provide the product as a whitesolid. Yield: 1.10 g, 2.20 mmol, 62%. LCMS m/z 501.0 [M+H⁺], Br isotopicpattern. ¹H NMR (400 MHz, CD₃OD), δ 8.09 (br s, 2H), 7.64 (t, J=8.0 Hz,1H), 7.53-7.56 (m, 1H), 7.44-7.48 (m, 2H), 7.23 (dd, J=12.1, 8.4 Hz,1H), 4.47-4.49 (m, 1H), 4.35-4.37 (m, 1H), 4.1 (dd, J=11.7, 1.6 Hz, 1H),3.94-4.01 (m, 1H), 3.9 (d, J=11.7 Hz, 1H), 3.13-3.21 (m, 1H), 2.96 (dd,J=13.2, 4.2 Hz, 1H), 2.75 (dd, J=13.4, 2.8 Hz, 1H), 1.88 (q, J=12.1 Hz,1H), 1.63-1.71 (m, 1H).

Step 3: Synthesis ofN-[(4aR,6R,8aS)-8a-(5-cyano-2,4-difluorophenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C14)

N-[(4aR,6R,8aS)-8a-(5-Bromo-2,4-difluorophenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C13) was converted to the product using the method described for thesynthesis ofN-[(6R)-6-[(benzyloxy)methyl]-8a-(5-cyano-2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C10) in Example 1. Yield: 98.5 mg, 0.220 mmol, 44%. LCMS m/z 446.2[M+H⁺]. ¹H NMR (400 MHz, CD₃OD), δ 8.06 (d, J=7.2 Hz, 2H), 7.85 (t,J=7.8 Hz, 1H), 7.54-7.57 (m, 1H), 7.45-7.49 (m, 2H), 7.37 (dd, J=12.1,9.2 Hz, 1H), 4.44-4.51 (m, 1H), 4.32-4.39 (m, 1H), 4.06-4.10 (m, 1H),3.89-4.0 (m, 2H), 3.11-3.19 (m, 1H), 2.96 (dd, J=13.3, 4.1 Hz, 1H), 2.75(dd, J=13.3, 2.9 Hz, 1H), 1.83-1.93 (m, 1H), 1.64-1.69 (m, 1H).

Step 4: Synthesis of5-[(4aR,6R,8aS)-2-amino-6-(fluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzonitrile(4)

N-[(4aR,6R,8aS)-8a-(5-Cyano-2,4-difluorophenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C14) was converted to the product using the method described for thesynthesis of5-[(4aR,6R,8aS)-2-amino-6-[(benzyloxy)methyl]-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzonitrile(2) in Example 2. Yield: 67.0 mg, 0.197 mmol, 88%. LCMS m/z 342.2[M+H⁺]. ¹H NMR (400 MHz, CD₃OD), δ 7.64 (t, J=7.9 Hz, 1H), 7.31 (dd,J=12.1, 9.2 Hz, 1H), 4.41-4.48 (m, 1H), 4.29-4.36 (m, 1H), 4.04 (dd,J=11, 2.4 Hz, 1H), 3.83-3.93 (m, 1H), 3.69 (d, J=11.1 Hz, 1H), 2.86-2.97(m, 2H), 2.69-2.73 (m, 1H), 1.82 (qd, J=12.4, 2.7 Hz, 1H), 1.52 (ddd,J=13.2, 4.2, 2.5 Hz, 1H).

Example 55-[(4aR,6R,8aS)-2-Amino-6-(methoxymethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzonitrile(5)

Step 1: Synthesis ofN-[(4aR,6R,8aS)-8a-(5-bromo-2,4-difluorophenyl)-6-(methoxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C15)

To C12 (100 mg, 0.201 mmol) in tetrahydrofuran (4 mL) was added sodiumhydride (60% in mineral oil, 22 mg, 0.54 mmol) and the reaction wasallowed to stir at room temperature for 30 minutes. Methyl iodide (16.7μL, 0.270 mmol) was added and the reaction was allowed to stir at roomtemperature for 16 hours. Saturated aqueous sodium bicarbonate was added(50 mL) and the aqueous was extracted with ethyl acetate (3×20 mL). Thecombined organics were washed with brine (10 mL), dried over sodiumsulfate, filtered and concentrated in vacuo to provide the product as ayellow solid. This was used in the next step without furtherpurification. Yield: 98.0 mg, 0.191 mmol, 95%. LCMS m/z 513.1 [M+H⁺], Brisotope.

Step 2: Synthesis ofN-[(4aR,6R,8aS)-8a-(5-cyano-2,4-difluorophenyl)-6-(methoxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C16)

N-[(4aR,6R,8aS)-8a-(5-Bromo-2,4-difluorophenyl)-6-(methoxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C15) was converted to the product using the method described for thesynthesis ofN-[(6R)-6-[(benzyloxy)methyl]-8a-(5-cyano-2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C10) in Example 1. Yield: 92.0 mg, 0.209 mmol, 110%. LCMS m/z 458.2[M+H⁺].

Step 3: Synthesis of5-[(4aR,6R,8aS)-2-amino-6-(methoxymethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzonitrile(5)

N-[(4aR,6R,8aS)-8a-(5-Cyano-2,4-difluorophenyl)-6-(methoxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C16) was converted to the product using the method described for thesynthesis of5-[(4aR,6R,8aS)-2-amino-6-[(benzyloxy)methyl]-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzonitrile(2) in Example 2. Yield: 13.2 mg, 38.0 μmol, 19%. LCMS m/z 354.2 [M+H⁺].¹H NMR (400 MHz, CD₃OD), δ 7.64 (t, J=7.8 Hz, 1H), 7.3 (dd, J=12, 9.1Hz, 1H), 4.01 (dd, J=11.1, 2.5 Hz, 1H), 3.76-3.82 (m, 1H), 3.66 (d,J=11.1 Hz, 1H), 3.45 (dd, J=10.3, 6.4 Hz, 1H), 3.39 (dd, J=10.3, 3.9 Hz,1H), 3.36 (s, 3H), 2.84-2.92 (m, 2H), 2.67-2.71 (m, 1H), 1.70-1.80 (m,1H), 1.50-1.55 (m, 1H).

Example 63-[(4aR,6S,8aS)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-chlorobenzonitrile(6)

Step 1: Synthesis of4-chloro-3-[(3aR,5S,7aS)-5-methyltetrahydro-1H-pyrano[3,4-c][1,2]oxazol-7a(7H)-yl]benzonitrile(C17)

To P2 (55 mg, 0.39 mmol) in toluene (3 mL) cooled to −78° C. was addedboron trifluoride-diethyl etherate (46.5%, 95 μL, 0.437 mmol). Thereaction was then allowed to warm to room temperature for 30 minutes atwhich point 3-bromo-4-chlorobenzonitrile (106 mg, 0.488 mmol) was addedas a solid. Once the solution became homogenous it was cooled to −78° C.at which point tert-butyllithium (1.7 M solution in pentanes, 0.514 mL,0.874 mmol) was added drop-wise. The reaction was allowed to stir at−78° C. for 20 minutes followed by addition of saturated aqueousammonium chloride solution (3 mL) and dichloromethane (6 mL). Thereaction was warmed to room temperature, and the organics wereseparated, dried over sodium sulfate, and concentrated in vacuo. Theresidue was carried into the next step without further purification.Yield: 75 mg, 0.266 mmol, 68%. LCMS m/z 281.1 [M+H⁺]C1 isotope pattern.

Step 2: Synthesis of3-[(3S,4R,6S)-3-amino-4-(hydroxymethyl)-6-methyltetrahydro-2H-pyran-3-yl]-4-chlorobenzonitrile(C18)

To crude C17 (75.0 mg, 0.270 mmol) in glacial acetic acid (1 mL) wasadded zinc dust (30.0 mg, 0.458 mmol). The reaction was stirred at roomtemperature for 1 hour at which point dichloromethane (10 mL) was added.The reaction mixture was then filtered through a pad of Celite and thefiltrate was concentrated in vacuo. The residue was taken up in methanol(1 mL) and loaded onto an Oasis® MCX cation exchange solid-phaseextraction cartridge (Waters, 12 mL, 1 g bed weight) and washed withdichloromethane (30 mL) and methanol (30 mL). The product was elutedfrom the column with a solution of ammonia in methanol (2 M, 20 mL) andthe filtrate was concentrated in vacuo to provide product that wasutilized in the next step without additional purification. Yield: 35.0mg, 0.124 mmol, 46%.

Step 3: Synthesis ofN-{[(3S,4R,6S)-3-(2-chloro-5-cyanophenyl)-4-(hydroxymethyl)-6-methyltetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide(C19)

To crude C18 (35.0 mg, 0.124 mmol) in dichloromethane (3 mL) was addedbenzoyl isothiocyanate (16.0 μL, 0.125 mmol) and the reaction wasallowed to stir at room temperature for 22 hours. The reaction mixturewas concentrated in vacuo to provide the product as a yellow oilyresidue, which was used in the subsequent step without furtherpurification. Yield: 60.0 mg, 0.131 mmol, 109%. LCMS m/z 442.2 [M−H⁺].

Step 4: Synthesis ofN-[(4aR,6S,8aS)-8a-(2-chloro-5-cyanophenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C20)

To a solution of C19 (60.0 mg, 0.134 mmol) and pyridine (41 μL, 0.51mmol) in dichloromethane (2.31 mL) cooled to −78° C. was addedtrifluoromethanesulfonic anhydride (45 μL, 0.27 mmol) drop-wise. Thereaction mixture was gradually warmed to 0° C. over 3 hours at whichpoint water (1 mL) was added. The aqueous was extracted withdichloromethane (2×2 mL). The combined organics were dried over sodiumsulfate, filtered and concentrated in vacuo. Silica gel chromatography(Gradient: 0% to 100% ethyl acetate in heptane) provided the product asa yellow residue. Yield: 16.0 mg, 38.0 μmol, 28%. LCMS m/z 426.2 [M+H⁺],Cl isotope pattern.

Step 5: Synthesis of3-[(4aR,6S,8aS)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-chlorobenzonitrile(6)

To a solution of C20 (16 mg, 38 μmol) in ethanol (1 mL) was addedhydrazine monohydrate (20 μL, 0.27 mmol). The reaction was stirred atroom temperature for 1 hour at which point the reaction mixture wasconcentrated in vacuo, dissolved in dimethyl sulfoxide (0.9 mL) andpurified by reverse phase HPLC (Column: Waters XBridge C18, 19×100 mm, 5μm; Mobile phase A: 0.03% ammonium hydroxide in water (v/v); Mobilephase B: 0.03% ammonium hydroxide in acetonitrile (v/v); Gradient: 20%to 50% B, linear over 8.5 minutes). Post purification QC conditions:(Column: Waters Atlantis dC18, 4.6×50 mm, 5 μm; Mobile phase A: 0.05%trifluoroacetic acid in water (v/v); Mobile phase B: 0.05%trifluoroacetic acid in acetonitrile (v/v); Gradient: 5.0% to 95% B,linear over 4.0 minutes; Flow rate: 2 mL/minute). Yield 1.80 mg, 4.44μmol, 12%. LC/MS m/z 322.2 [M+H⁺], Cl isotope pattern. Analyticalretention time: 1.8 minutes.

Example 73-[(4aR,6S,8aS)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]benzonitrile(7)

Step 1: Synthesis of3-[(3aR,5S,7aS)-5-methyltetrahydro-1H-pyrano[3,4-c][1,2]oxazol-7a(7H)-yl]benzonitrile(C21)

P2 was converted to the product using the method described for thesynthesis of4-chloro-3-[(3aR,5S,7aS)-5-methyltetrahydro-1H-pyrano[3,4-c][1,2]oxazol-7a(7H)-yl]benzonitrile(C17) in Example 6. The resulting product was used in the next stepwithout further purification. Yield: 173 mg, 0.708 mmol, 100%. GCMS m/z244 [M⁺].

Step 2: Synthesis of3-[(3S,4R,6S)-3-amino-4-(hydroxymethyl)-6-methyltetrahydro-2H-pyran-3-yl]benzonitrile(C22)

3-[(3aR,5S,7aS)-5-Methyltetrahydro-1H-pyrano[3,4-c][1,2]oxazol-7a(7H)-yl]benzonitrile(C21) was converted to the product using the method described for thesynthesis of3-[(3S,4R,6S)-3-amino-4-(hydroxymethyl)-6-methyltetrahydro-2H-pyran-3-yl]-4-chlorobenzonitrile(C18) in Example 6. The resulting product was used in the next stepwithout further purification. Yield: 105 mg, 0.426 mmol, 60%. LCMS m/z247.1 [M+H⁺].

Step 3: Synthesis ofN-{[(3S,4R,6S)-3-(3-cyanophenyl)-4-(hydroxymethyl)-6-methyltetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide(C23)

3-[(3S,4R,6S)-3-Amino-4-(hyd roxymethyl)-6-methyltetrahydro-2H-pyran-3-yl]benzonitrile (C22) was converted to the product usingthe method described for the synthesis ofN-{[(3S,4R,6S)-3-(2-chloro-5-cyanophenyl)-4-(hydroxymethyl)-6-methyltetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide(C19) in Example 6. The resulting product was used in the next stepwithout further purification. Yield: 118 mg, 0.288 mmol, 68%. LCMS m/z410.2 [M+H⁺].

Step 4: Synthesis ofN-[(4aR,6S,8aS)-8a-(3-cyanophenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C24)

N-{[(3S,4R,6S)-3-(3-Cyanophenyl)-4-(hydroxymethyl)-6-methyltetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide(C23) was converted to the product using the method described for thesynthesis ofN-[(4aR,6S,8aS)-8a-(2-chloro-5-cyanophenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C20) in Example 6. The resulting product was used in the next stepwithout further purification. Yield: 45.0 mg, 0.115 mmol, 40%. LCMS m/z392.2 [M+H⁺].

Step 5: Synthesis of3-[(4aR,6S,8aS)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]benzonitrile(7)

N-[(4aR,6S,8aS)-8a-(3-Cyanophenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C24) was converted to the product using the method described for thesynthesis of3-[(4aR,6S,8aS)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-chlorobenzonitrile(6) in Example 6. Purification by reverse phase HPLC (Column: WatersSunfire C18, 19×100 mm, 5 μm; Mobile phase A: 0.05% trifluoroacetic acidin water (v/v); Mobile phase B: 0.05% trifluoroacetic acid inacetonitrile (v/v); Gradient: 20.0% to 60% B, linear over 8.5 minutes).QC conditions: (Column: Waters Atlantis dC18, 4.6×50 mm, 5 μm; Mobilephase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phase B:0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 5.0% to 95%B, linear over 4.0 minutes; Flow rate: 2 mL/minute). Yield 22.5 mg, 0.08mmol, 50%. LC/MS m/z 288.2 [M+H⁺]. Retention time: 1.62 minutes.

Example 8(4aR,6R,8aS)-8a-(2,4-Difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine(8)

Step 1. Synthesis of tert-butyl{5-[(4aR,6R,8aS)-2-(benzoylamino)-6-(fluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzyl}carbamate(C25)

To an ice-cooled (0° C.) heterogeneous mixture ofN-[(4aR,6R,8aS)-8a-(5-cyano-2,4-difluorophenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C14) (0.328 g, 0.736 mmol) in methanol (41 mL) was added di-tert-butyldicarbonate (0.321 g, 1.47 mmol) and nickel(II) chloride hexahydrate (18mg, 74 μmol) followed by the careful portion-wise addition of sodiumborohydride (0.195 g, 5.15 mmol). The resulting black mixture wasstirred at 0° C. for 20 minutes, then at room temperature for 16 hours.After that time, N-(2-aminoethyl)ethane-1,2-diamine (80 μL, 0.736 mmol)was added at room temperature and the reaction mixture was left stirringfor 2 hours. The reaction mixture was partitioned between ethyl acetate(200 mL) and a saturated aqueous solution of ammonium chloride (500 mL).The aqueous layer was further extracted with ethyl acetate (2×100 mL).The combined organics were then washed sequentially with an aqueoussaturated sodium bicarbonate solution (500 mL) and with brine (200 mL),dried over sodium sulfate, filtered and concentrated in vacuo to givethe product as a black oily residue (0.59 g), which was taken directlyto the following step. LCMS m/z 550 [M+H⁺].

Step 2. Synthesis ofN-[(4aR,6R,8aS)-8a-[5-(aminomethyl)-2,4-difluorophenyl]-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C26)

A solution of hydrogen chloride in dioxane (4.0 M, 10 mL, 41 mmol) wasadded to tert-butyl{5-[(4aR,6R,8aS)-2-(benzoylamino)-6-(fluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzyl}carbamate(C25) (0.8277 g, 1.506 mmol) at room temperature. The reaction mixturewas stirred overnight and then concentrated under reduced pressure toyield a brown solid. The solid was partitioned between a 1:1 solution ofethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (100mL). The organics were separated and the aqueous layer was extractedfurther with ethyl acetate (2×100 mL). The combined organics were thenwashed with brine (200 mL), dried over sodium sulfate, filtered andconcentrated under reduced pressure to yield the product as a brownsolid (0.598 g), which was taken directly to the following step. LCMSm/z 450 [M+H⁺]. ¹H NMR (400 MHz, CD₃OD), characteristic peaks: δ8.11-8.13 (m, 2H), 7.44-7.57 (m, 3H), 7.09 (dd, J=12.3, 9.6 Hz, 1H),4.49-4.51 (m, 1H), 4.37-4.39 (m, 1H), 3.20-3.23 (m, 1H), 3.01 (dd,J=13.0, 4.2 Hz, 1H), 2.77 (dd, J=13.0, 2.8 Hz, 1H), 1.89 (m, 1H), 1.70(ddd, J=13.4, 4.1, 2.2 Hz, 1H).

Step 3. Synthesis ofN-[(4aR,6R,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C27)

A solution ofN-[(4aR,6R,8aS)-8a-[5-(aminomethyl)-2,4-difluorophenyl]-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C26) (0.598 g, 1.33 mmol) in acetonitrile (13 mL) was treated withtriethylamine (0.277 mL, 2.00 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.288 mL, 2.00 mmol). The reaction vial wassealed and the resulting solution was stirred at 70° C. for 16 hours.The reaction mixture was cooled to room temperature and concentratedunder reduced pressure to yield a brown solid. The solid was partitionedbetween water (100 mL) and ethyl acetate (100 mL). The organics wereisolated and the aqueous layer was extracted further with ethyl acetate(2×50 mL). The combined organics were then washed with brine (100 mL),dried over sodium sulfate, filtered and concentrated under reducedpressure. Purification via silica gel chromatography (Gradient: 0% to60% ethyl acetate in heptane) afforded the product as a white solid.Yield: 0.4064 g, 57%. LCMS m/z 532.0 [M+H⁺]. ¹H NMR (400 MHz, CD₃OD) δ8.12 (br d, J=8 Hz, 2H), 7.45-7.59 (m, 3H), 7.08 (dd, J=12.3, 9.6 Hz,1H), 4.50-4.52 (m, 1H), 4.38-4.40 (m, 1H), 4.15 (dd, J=12.1, 2 Hz, 1H),3.90-3.94 (m, 3H), 3.00 (dd, J=13.4, 4.0 Hz, 1H), 2.77 (dd, J=13.1, 2.9Hz, 1H), 1.87-1.96 (m, 1H), 1.69-1.72 (m, 1H).

Step 4. Synthesis of(4aR,6R,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine(8)

1,8-Diazabicyclo[5.4.0]undec-7-ene (0.084 mL, 0.534 mmol) was added to asolution ofN-[(4aR,6R,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C27) (0.4064 g, 0.7650 mmol) in methanol (30 mL). The resultingsolution was heated to 70° C. until complete consumption of startingmaterial. The reaction mixture was concentrated under reduced pressureto yield product as an orange oily residue. Purification via silica gelchromatography (Gradient: 0% to 20% methanol in dichloromethane)afforded the product as a white solid. Yield: 0.273 g (84%). LCMS m/z428 [M+H⁺]. ¹H NMR (400 MHz, CD₃OD) δ 7.38 (t, J=8.8 Hz, 1H), 6.98 (dd,J=12.2, 9.7 Hz, 1H), 4.42-4.48 (m, 1H), 4.30-4.37 (m, 1H), 4.09 (dd,J=11.2, 2.0 Hz, 1H), 3.86-3.90 (m, 3H), 3.72 (d, J=11.2 Hz, 1H),3.13-3.18 (m, 2H), 2.90-2.97 (m, 2H), 2.70 (dd, J=12.4, 2.6 Hz, 1H),1.76-1.87 (m, 1H), 1.52 (ddd, J=13.1, 4.0, 2.3 Hz, 1H).

Example 9(4aR,6S,8aS)-8a-(2,4-Difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine(9)

Step 1. Synthesis ofN-[(4aR,6S,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C28)

Lithium triethylborohydride (1.13 mL, 1.13 mmol) was added to a solutionofN-[(4aR,6R,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C27) (60 mg, 0.11 mmol) in tetrahydrofuran (4 mL). The reaction mixturewas allowed to stir at room temperature for 16 hours and thenpartitioned between ethyl acetate (25 mL) and a saturated aqueoussolution of sodium bicarbonate (50 mL). The layers were separated andthe aqueous layer was extracted further with ethyl acetate (3×25 mL).The combined organics were then washed sequentially with water (100 mL)and with brine (100 mL), dried over sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure to yield a white solid.The organic crude was re-dissolved in dichloromethane (20 mL) and theresulting solution was washed with 1 N sodium hydroxide (3×25 mL), water(100 mL), and brine (100 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated under reduced pressure to provide theproduct as an orange solid (60 mg), which was taken directly to thefollowing step. LCMS m/z 514 [M+H⁺].

Step 2. Synthesis of(4aR,6S,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine(9)

N-[(4aR,6S,8aS)-8a-(2,4-Difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C28) was converted to the product according to the method described forthe synthesis of(4aR,6R,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine(8) in Example 8. Purification via silica gel chromatography (Gradient:0% to 20% methanol in dichloromethane) afforded the product as a whitesolid. Yield: 12 mg, 25%. LCMS m/z 410 [M+H⁺]. ¹H NMR (400 MHz, CD₃OD) δ7.39 (t, J=8.7 Hz, 1H), 7.00 (dd, J=12.3, 9.6 Hz, 1H), 4.07 (dd, J=11.3,2.0 Hz, 1H), 3.70-3.79 (m, 2H), 3.18 (q, J=9.3 Hz, 2H), 2.91-3.02 (m,2H), 2.73 (dd, J=12.5, 2.7 Hz, 1H), 1.58-1.73 (m, 2H), 1.24 (d, J=8.0Hz, 3H).

Example 103-[(4aR,6R,8aS)-2-Amino-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile(10)

Step 1. Synthesis of(3aR,5R,7aS)-5-[(benzyloxy)methyl]-7a-(5-bromo-2-fluorophenyl)hexahydro-1H-pyrano[3,4-c][1,2]oxazole(C29)

A solution of(3aR,5R)-5-[(benzyloxy)methyl]-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole(P1) (10.0 g, 40.4 mmol) in toluene (404 mL) was cooled down to −78° C.and then boron trifluoride-diethyl etherate (46.5%, 10.8 mL, 40.8 mmol)was added. The resulting solution was allowed to stir at the sametemperature for 30 minutes, with fast stirring. After that time,4-bromo-1-fluoro-2-iodobenzene (12.3 g, 40.8 mmol) was added to thereaction mixture, followed by the slow addition (temperature nevervaried more than 5° C.) of n-butyllithium (2.5 M in hexanes; 16.3 mL,42.7 mmol). The resulting solution was allowed to stir at −78° C. for 90minutes. At this time, a saturated aqueous solution of ammonium chloride(20 mL) was added to the reaction mixture at −78° C. The reactionmixture was warmed to room temperature and partitioned between ethylacetate (400 mL) and water (800 mL). The organics were separated and theaqueous layer was extracted with additional ethyl acetate (3×200 mL).The combined organics were then washed with brine (200 mL), dried oversodium sulfate, filtered and concentrated under reduced pressure toyield a clear oily residue. Purification via silica gel chromatography(Gradient: 10% to 70% ethyl acetate in heptane) afforded the product asan orange solid. Yield: 11.5 g, 27.1 mmol, 67%. ¹H NMR (400 MHz, CD₃OD)δ 8.01 (dd, J=6.9, 2.6 Hz, 1H), 7.47 (ddd, J=8.8, 4.4, 2.7 Hz, 1H),7.38-7.28 (m, 4H), 7.07 (dd, J=11.6, 8.7 Hz, 1H), 4.58 (s, 2H), 4.10(dd, J=11.6, 2.4 Hz, 1H), 3.82-3.78 (m, 2H), 3.72 (d, J=7.2 Hz, 1H),3.61-3.55 (m, 2H), 3.52 (dd, J=8.8, 4.7 Hz, 1H), 3.16-3.10 (m, 1H), 1.86(ddd, J=14.1, 7.0, 2.2 Hz, 1H), 1.59 (dtd, J=13.7, 11.8, 1.7 Hz, 1H).

Step 2. Synthesis of[(2R,4R,5S)-5-amino-2-[(benzyloxy)methyl]-5-(5-bromo-2-fluorophenyl)tetrahydro-2H-pyran-4-yl]methanol(C30)

Molybdenum hexacarbonyl (0.702 g, 2.60 mmol) was added to a solution of(3aR,5R)-5-[(benzyloxy)methyl]-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazoleC29 (1.00 g, 2.37 mL) in acetonitrile (10 mL) and water (0.7 mL). Theresulting solution was refluxed for 30 minutes and then cooled down toroom temperature. Once at room temperature, sodium borohydride (0.089 g,2.37 mmol) was added to the reaction mixture. The resulting solution wasthen heated to reflux for another 3 hours. The reaction mixture wascooled down to room temperature, quenched with methanol (100 mL),filtered through Celite and the resulting Celite pad was washed withethyl acetate (3×200 mL). The combined filtrate was washed sequentiallywith a saturated aqueous solution of sodium bicarbonate (2×250 mL) andwith brine (200 mL) and dried over sodium sulfate. The resultingsolution was filtered and concentrated under reduced pressure to givethe product as a black oily residue, which was taken directly to thefollowing step. LCMS m/z 425.2 [M+H⁺].

Step 3. Synthesis ofN-{[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(5-bromo-2-fluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide(C31)

Benzoyl isothiocyanate (3.40 mL, 25.3 mmol) was added to a solution of[(2R,4R,5S)-5-amino-2-[(benzyloxy)methyl]-5-(5-bromo-2-fluorophenyl)tetrahydro-2H-pyran-4-yl]methanol(C30) (10.84 g, 25.55 mmol) in dichloromethane (255 mL). The reactionmixture was stirred at room temperature for 48 hours and thenconcentrated under reduced pressure to afford the product as a lightyellow solid (9.49 g), which was taken directly to the following step.LCMS m/z 587.0 [M−H+].

Step 4. Synthesis ofN-[(4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(5-bromo-2-fluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C32)

A solution ofN-{[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(5-bromo-2-fluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide(C31) (9.49 g, 16.2 mmol) and pyridine (4.94 mL, 61.4 mmol) indichloromethane (278 mL) was cooled to −50° C. Trifluoromethanesulfonicanhydride (5.44 mL, 32.3 mmol) was added drop-wise to the solution andthe mixture was gradually warmed to 0° C. After 2 hours, the reactionmixture was partitioned between dichloromethane (1 L) and water (500mL). The organic layer was washed with dichloromethane (2×250 mL) andthe combined organics were then washed with brine (500 mL). Theresulting organic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo to yield an orange oily residue. Purification viasilica gel chromatography (Gradient: 0% to 60% ethyl acetate in heptane)afforded the product as an orange solid. Yield: 5.53 g, 60%. LCMS m/z571.2 [M+H⁺]. ¹H NMR (400 MHz, CD₃OD) characteristic peaks: δ 8.12 (d,J=7.4 Hz, 2H), 7.43-5.58 (m, 5H), 7.12-7.32 (m, 6H), 4.51-4.60 (m, 2H),4.10-4.13 (m, 1H), 3.87-3.91 (m, 1H), 3.55-3.63 (m, 2H), 3.18-3.21 (m,1H), 2.94 (dd, J=13.2, 4.0 Hz, 1H), 2.74 (dd, J=13.1, 2.9 Hz, 1H),1.90-1.99 (m, 1H), 1.67-1.72 (m, 1H).

Step 5. Synthesis ofN-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C33)

Boron trichloride (45.8 mL, 45.8 mmol) was added to a solution ofN-[(4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(5-bromo-2-fluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C32) (8.70 g, 15.3 mmol) in dichloromethane (76 mL) at 0° C., whilemaintaining the internal temperature below 5° C. The heterogeneousmixture was allowed to stir for 10 minutes at 0° C. and then at roomtemperature for 16 hours. The reaction mixture was then quenched bydrop-wise addition of methanol (100 mL). The methanol solution wasrefluxed for 15 minutes and then concentrated under reduced pressure.The residue was re-dissolved in dichloromethane (100 mL) and washedsequentially with 1 N sodium hydroxide (2×100 mL) and with brine (100mL), dried over sodium sulfate and filtered. Purification via silica gelchromatography (Gradient: 30% to 100% ethyl acetate in heptane) affordedthe product as an off-white solid. Yield: 4.98 g, 68%. LCMS m/z 410[M+H⁺]. ¹H NMR (400 MHz, CD₃OD) δ 8.13 (d, J=6.8 Hz, 1H), 7.59-7.45 (m,4H), 7.16 (dd, J=12.1, 8.6 Hz, 1H), 4.15-4.11 (m, 1H), 3.91 (d, J=11.9Hz, 1H), 3.79-3.73 (m, 1H), 3.59 (d, J=5.1 Hz, 1H), 3.21 (br s, 1H),2.96 (dd, J=13.0, 4.0 Hz, 1H), 2.76 (dd, J=13.2, 2.8 Hz, 1H), 1.81-1.90(m, 1H), 1.72-1.68 (m, 1H).

Step 6. Synthesis of(4aR,6R,8aS)-2-(benzoylamino)-8a-(5-bromo-2-fluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazine-6-carboxylicacid (C34)

N-Methylmorpholine N-oxide monohydrate (3.38 g, 25.0 mmol) andtetrapropylammonium perruthenate (0.147 g, 0.417 mmol) were added to asolution ofN-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C33) (2.0 g, 4.17 mmol) in acetonitrile (75 mL). The reaction mixturewas allowed to stir at room temperature for 16 hours. 2-Propanol (200mL) was added to the reaction mixture and the resulting solution wasleft stirring at room temperature for 35 minutes. After that time, thereaction mixture was concentrated under reduced pressure. The oilyresidue was partitioned between aqueous 0.25 M sodium hydroxide (200 mL)and a 1:1 solution of diethyl ether:ethyl acetate (200 mL each). Thelayers were isolated and the organic layer was washed with aqueous 0.25M sodium hydroxide (3×200 mL). The combined aqueous layers were thenacidified to pH 1 with 2 M aqueous hydrochloric acid (300 mL). The nowheterogeneous mixture was extracted with ethyl acetate (4×200 mL). Thecombined organics were then dried over sodium sulfate, filtered andconcentrated under reduced pressure to give the product (2.34 g) as apurple solid, which was taken directly to the following step. LCMS m/z495.1 [M+H⁺]. ¹H NMR (400 MHz, CD₃OD) δ 8.08-8.11 (m, 1H), 7.50-7.64 (m,4H), 7.17-7.22 (m, 1H), 4.39 (dd, J=11.8, 2.8 Hz, 1H), 4.20 (d, J=12.1Hz, 1H), 4.04-4.07 (m, 1H), 3.06 (dd, J=12.9, 4.3 Hz, 1H), 2.92 (dd,J=13.7, 3.1 Hz, 1H), 2.13-2.18 (m, 1H), 2.05-2.09 (m, 1H), 1.99-2.02 (m,4H).

Step 7. Synthesis of(4aR,6R,8aS)-2-(benzoylamino)-8a-(5-bromo-2-fluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazine-6-carboxylate(C35)

To a solution of(4aR,6R,8aS)-2-(benzoylamino)-8a-(5-bromo-2-fluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazine-6-carboxylicacid (C34) (1.00 g, 2.03 mmol) in dichloromethane (15 mL) was addedoxalyl chloride (0.536 mL, 6.24 mmol) in a drop-wise manner, followed byslow addition of N,N-dimethylformamide (0.025 mL, 0.32 mmol). Theresulting solution was stirred at room temperature for 15 minutes. Thereaction mixture was quenched with methanol (20 mL) and concentratedunder reduced pressure. Purification via silica gel chromatography(Gradient: 30% to 100% ethyl acetate in heptane) afforded the product asa yellow solid. Yield: 1.09 g (quantitative). LCMS m/z 507.1 [M+H⁺].

¹H NMR (400 MHz, CD₃OD) δ 8.04-8.07 (m, 1H), 7.58-7.76 (m, 4H), 7.24(dd, J=12.3, 8.6 Hz, 1H), 4.49 (dd, J=11.7, 2.7 Hz, 1H), 4.22 (s, 1H),4.03-4.12 (m, 1H), 3.53 (dd, J=12.0, 4.2 Hz, 1H), 3.21 (td, J=13.6, 3.3Hz, 2H), 2.21 (ddd, J=14.0, 4.6, 2.5 Hz, 1H).

Step 8. Synthesis ofN-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C36)

A solution of propan-2-one oxime (0.216 g, 2.96 mmol) in tetrahydrofuran(10 mL) was cooled to 0° C. To this solution was added n-butyllithium(2.5 M in hexanes, 2.40 mL, 6.00 mmol) in a drop-wise manner. Theresulting solution was allowed to warm to room temperature and leftstirring at room temperature for 25 minutes. The resulting solution wascooled again to 0° C., followed by a drop-wise addition of methyl(4aR,6R,8aS)-2-(benzoylamino)-8a-(5-bromo-2-fluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazine-6-carboxylate(C35) (1.09 g, 2.03 mmol) in tetrahydrofuran (3 mL). The reactionmixture was allowed to warm to room temperature and was left stirringfor 25 minutes. The reaction mixture was cooled to 0° C. again, andsulfuric acid (0.840 mL, 15.8 mmol) was added in a drop-wise manner. Thereaction mixture was allowed to warm up to room temperature and was leftstirring for 16 hours at room temperature. The reaction mixture wasbasified to pH 12 with sodium hydroxide (5 N, ˜4 mL) and then extractedwith ethyl acetate (3×100 mL). The combined organics were dried oversodium sulfate, filtered and concentrated under reduced pressure to givean oily residue. Purification via silica gel chromatography (Gradient:0% to 100% ethyl acetate in heptane) afforded the product as a whitesolid. Yield: 330 mg, 63%. LCMS m/z 532.2 [M+H⁺]. ¹H NMR (400 MHz,CD₃OD) δ 8.12 (br s, 1H), 7.47-7.61 (m, 4H), 7.19 (dd, J=12.0, 8.9 Hz,1H), 4.97 (br d, J=9.4 Hz, 1H), 4.31 (dd, J=11.8, 1.5 Hz, 1H), 4.00-4.14(m, 2H), 3.00 (dd, J=13.2, 4.0 Hz, 1H), 2.83 (dd, J=13.1, 2.9 Hz, 1H),2.10 (d, J=12.1 Hz, 1H).

Step 9. Synthesis ofN-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C37)

N-[(4aR,6R,8aS)-8a-(5-Bromo-2-fluorophenyl)-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C36) (0.100 g, 0.189 mmol), zinc cyanide (0.027 g, 0.227 mmol),tetrakis(triphenylphosphine)palladium(0) (0.127 g, 0.110 mmol) andN,N-dimethylformamide (6 mL) were added to an Emrys microwave reactionvial. The vial was sealed and purged with nitrogen gas for 10 minuteswith stirring. After that time, the vial was placed on a Biotagemicrowave processor and heated to 80° C. for 3 hours. The reactionmixture was partitioned between ethyl acetate (100 mL) and a saturatedaqueous solution of sodium bicarbonate (100 mL). The layers wereseparated and aqueous layer was extracted further with ethyl acetate(3×50 mL). The combined organics were washed with brine (200 mL), driedover sodium sulfate, filtered and concentrated in vacuo. Purificationvia silica gel chromatography (Gradient: 30% to 100% ethyl acetate inheptane) afforded the product as an off-white solid. Yield: 51 mg, 57%.LCMS m/z 477.3 [M+H⁺]. ¹H NMR (400 MHz, CD₃OD) characteristic peaks: δ8.09 (br s, 2H), 7.83-7.87 (m, 2H), 7.40-7.59 (m, 4H), 4.97 (d, J=9.2Hz, 1H), 4.30 (dd, J=11.7, 1.6 Hz, 1H), 4.00-4.13 (m, 2H), 2.97 (dd,J=12.9, 3.9 Hz, 1H), 2.82 (dd, J=13.2, 3.0 Hz, 1H).

Step 10. Synthesis of3-[(4aR,6R,8aS)-2-amino-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile(10)

Methylamine (8 M in ethanol, 1.34 mmol) was added to a solution ofN-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C37) (0.051 g, 0.11 mmol) in ethanol (4 mL). The resulting solution wasallowed to stir at room temperature for 16 hours. The reaction mixturewas concentrated under reduced pressure to give a yellow oily residue.Purification via silica gel chromatography (Gradient: 0% to 15% methanolin dichloromethane) afforded the product as an off-white solid. Yield:25 mg, 63%. LCMS m/z 373.1 [M+H⁺]. ¹H NMR (400 MHz, CD₃OH) δ 7.78 (ddd,J=8.5, 4.5, 2.2 Hz, 1H), 7.69 (dd, J=7.2, 2.2 Hz, 1H), 7.35 (dd, J=8.6,11.3 Hz, 1H), 6.26 (s, 1H), 4.89 (dd, J=11.9, 2.5 Hz, 1H), 4.25 (dd,J=11.2, 2.2 Hz, 1H), 3.80 (d, J=11.2 Hz, 1H), 3.08-3.14 (m, 1H), 2.89(dd, J=12.7, 4.1 Hz, 1H), 2.78 (dd, J=12.7, 2.9 Hz, 1H), 2.28 (s, 3H),2.10-2.22 (m, 1H), 1.91-1.96 (m, 1H).

Example 113-[(4aR,6R,8aS)-2-Amino-6-(4-methyl-1,3-oxazol-2-yl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile(11)

Step 1. Synthesis of(4aR,6R,8aS)-2-(benzoylamino)-8a-(5-bromo-2-fluorophenyl)-N-(1-hydroxypropan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazine-6-carboxamide(C38)

Diisopropylethylamine (0.706 mL, 4.05 mmol) andO-(2-oxo-1(2H)pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.662 g, 2.23 mmol) were added to a solution of(4aR,6R,8aS)-2-(benzoylamino)-8a-(5-bromo-2-fluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazine-6-carboxylicacid (C34) (1.00 g, 2.03 mmol) in N,N-dimethylformamide (22 mL). Theresulting solution was allowed to stir at room temperature for 30minutes. Additional diisopropylethylamine (0.7 mL, 4.05 mmol) andO-(2-oxo-1(2H)pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.6 g, 2 mmol) were added to the reaction mixture and the resultingsolution was allowed to stir at room temperature for an additional 60minutes. Then 2-amino-1-propanol (0.632 mL, 8.11 mmol) was added in oneportion. The resulting black solution was allowed to stir at roomtemperature for 16 hours. The reaction mixture was partitioned betweenan aqueous saturated solution of sodium bicarbonate (100 mL), water (100mL) and diethyl ether (100 mL). The organic layer was isolated and theaqueous layer was further extracted with diethyl ether (3×100 mL). Thecombined organics were then washed with water (100 mL), brine (100 mL),dried over sodium sulfate and concentrated to give the product (897 mg,80%), which was used directly in the following step. LCMS m/z 552.2[M+H⁺]. ¹H NMR (400 MHz, CD₃OH) characteristic peaks δ 8.11 (br s, 2H),7.46-7.59 (m, 4H), 7.17 (dd, J=12.0, 9.1 Hz, 1H), 4.20 (d, J=11.9 Hz,1H), 3.96-4.12 (m, 2H).

Step 2. Synthesis of(4aR,6R,8aS)-2-(benzoylamino)-8a-(5-bromo-2-fluorophenyl)-N-(1-oxopropan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazine-6-carboxamide(C39)

Dess-Martin periodinane (1.04 g, 2.44 mmol) was added to a solution of(4aR,6R,8aS)-2-(benzoylamino)-8a-(5-bromo-2-fluorophenyl)-N-(1-hydroxypropan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazine-6-carboxamide(C38) (0.897 g, 1.63 mmol) in dichloromethane (75 mL). The resultingsolution was left stirring overnight at room temperature. The reactionmixture was diluted with diethyl ether (100 mL), a saturated aqueoussolution of sodium bicarbonate (50 mL) and a 10% aqueous solution ofsodium thiosulfate (50 mL). The layers were separated and the resultingaqueous layer was further extracted with diethyl ether (2×100 mL). Thecombined organics were then washed with water (100 mL), brine (100 mL),dried over sodium sulfate, filtered and concentrated under reducedpressure to give the product as a white solid. Yield 747 mg, 84%. LCMSm/z 532.1 [M+H⁺]. ¹H NMR (400 MHz, CD₃OD) characteristic peaks: δ 9.47(d, J=6.7 Hz, 1H), 8.11 (br d, J=6.7 Hz, 2H), 7.46-7.60 (m, 4H), 7.18(dd, J=12.1, 9.2 Hz, 1H), 4.19-4.31 (m, 2H), 4.01-4.13 (m, 1H).

Step 3. Synthesis ofN-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(4-methyl-1,3-oxazol-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C40)

Methyl N-(triethylammoniumsulfonyl)carbamate (Burgess reagent) (0.811 g,3.40 mmol) was added to a solution of(4aR,6R,8aS)-2-(benzoylamino)-8a-(5-bromo-2-fluorophenyl)-N-(1-oxopropan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazine-6-carboxamide(C39) (0.747 g, 1.36 mmol) in toluene (34 mL). The resulting solutionwas stirred at room temperature for 10 minutes, followed by heating to65° C. for 16 hours. The reaction mixture was concentrated under reducedpressure. Purification via silica gel chromatography (Gradient: 0% to100% ethyl acetate in heptane) afforded the product as a yellow oilyresidue. Yield: 417 mg, 58%. LCMS m/z 532.1 [M+H⁺]. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (br s, 2H), 7.36-7.54 (m, 5H), 7.36 (q, J=1.2 Hz, 1H),7.01-7.06 (m, 1H), 4.83 (dd, J=12.0, 2.4 Hz, 1H), 4.31 (dd, J=11.9, 1.6Hz, 1H), 3.07 (dd, J=13.0, 3.8 Hz, 1H), 2.70 (m, 1H), 2.58-2.54 (m, 1H),2.17 (d, J=1.7 Hz, 3H), 2.08-2.14 (m, 1H).

Step 4. Synthesis ofN-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(4-methyl-1,3-oxazol-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C41)

N-[(4aR,6R,8aS)-8a-(5-Bromo-2-fluorophenyl)-6-(4-methyl-1,3-oxazol-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C40) was converted to the product using the method described forsynthesis ofN-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C37) in Example 10. The product was obtained as a white solid. Yield:227 mg, 126%. LCMS m/z 477.2 [M+H⁺]. ¹H NMR (400 MHz, CD₃OH) δ 8.09 (brs, 2H), 7.83-7.86 (m, 2H), 7.61 (q, J=2.3 Hz, 1H), 7.55-7.65 (m, 2H),7.40-7.51 (m, 3H), 4.91 (dd, J=11.8, 2.4 Hz, 1H), 4.35 (dd, J=11.9, 1.6Hz, 1H), 4.00-4.13 (m, 2H), 2.97 (dd, J=13.1, 3.7 Hz, 1H), 2.82 (dd,J=13.2, 2.8 Hz, 1H), 2.38-2.47 (m, 1H), 2.15 and 2.01 (d, J=3.8 Hz, 3H),2.03-2.07 (m, 1H).

Step 5. Synthesis of3-[(4aR,6R,8aS)-2-amino-6-(4-methyl-1,3-oxazol-2-yl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile(11)

Methylamine (8 M in ethanol, 7.1 mL, 57.1 mmol) was added to a solutionofN-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(4-methyl-1,3-oxazol-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C41) (0.227 g, 0.48 mmol) in ethanol (12 mL). The resulting solutionwas allowed to stir at room temperature for 16 hours. The reactionmixture was concentrated under reduced pressure to give a yellow oilyresidue. Purification via silica gel chromatography (Gradient: 0% to 20%methanol in dichloromethane) afforded the product as an off-white solid.Yield: 144 mg, 81%. LCMS m/z 374.1 [M+H⁺]. ¹H NMR (400 MHz, CD₃OH) δ7.77 (ddd, J=8.5, 4.5, 2.2 Hz, 1H), 7.68 (dd, J=7.2, 2.3 Hz, 1H), 7.61(q, J=2.3 Hz, 1H), 7.35 (dd, J=12.1, 8.6 Hz, 1H), 4.82 (dd, J=11.9, 2.5Hz, 1H), 4.25 (dd, J=11.2, 2.2 Hz, 1H), 3.79 (d, J=11.2 Hz, 1H),3.06-3.13 (m, 1H), 2.89 (dd, J=12.7, 4.1 Hz, 1H), 2.78 (dd, J=12.7, 2.9Hz, 1H), 2.33-2.43 (m, 1H), 2.15 (d, J=1.4 Hz, 3H), 1.87-1.91 (m, 1H).

Example 123-[(4aR,6R,8aS)-2-Amino-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile(12)

Step 1. Synthesis ofN-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-formyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C42)

Triethylamine (6.94 mL, 50.0 mmol), dimethyl sulfoxide (4.14 mL, 58.3mmol) and pyridine-sulfur trioxide complex (5.41 g, 33.3 mmol) wereadded to a solution ofN-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C33) (2.00 g, 4.17 mmol) in dichloromethane (420 mL). The resultingsolution was allowed to stir at room temperature for 16 hours. Thereaction mixture was diluted with water (200 mL) and brine (200 mL). Theresulting biphasic solution was left stirring at room temperature for 10minutes. The organic layer was then isolated and the resulting aqueouslayer was back extracted with dichloromethane (3×100 mL). The combinedorganics were washed with water (2×200 mL), aqueous 0.2 N hydrochloricacid (200 mL) and brine (200 mL), dried over sodium sulfate, filteredand concentrated. Purification via silica gel chromatography (Gradient:20% to 100% ethyl acetate in heptane) afforded the product as a whitesolid. Yield 1.10 g, 55%. ¹H NMR (400 MHz, DMSO-d₆) characteristicpeaks: δ 9.60 (s, 1H), 8.10 (br d, J=7.6 Hz, 2H), 7.47-7.67 (m, 5H),7.32 (dd, J=12.1, 8.8 Hz, 1H), 4.32 (d, J=9.8 Hz, 1H), 3.07-3.11 (m,1H), 2.67-2.88 (m, 2H), 1.96-2.00 (m, 1H), 1.67-1.74 (m, 1H).

Step 2. Synthesis ofN-{(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-[(E)-2-methoxyethenyl]-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl}benzamide(C43)

A suspension of oven-dried (methoxymethyl)triphenylphosphonium chloride(2.56 g, 7.46 mmol) in tetrahydrofuran (41 mL) was cooled to 0° C. Tothis solution was added potassium tert-butoxide (1.0 M intetrahydrofuran, 6.41 mL, 6.41 mmol) at a very slow rate such that theinternal temperature did not exceed 5° C. The resulting bright orangesolution was left stirring at the same temperature for 5 minutes. It wasthen allowed to warm up to room temperature and was left stirring foranother 30 minutes. The reaction mixture was cooled down to 0° C. and asolution ofN-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-formyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C42) (1.00 g, 2.10 mmol) in tetrahydrofuran (18 mL) was then addedslowly. Once the addition was completed, the resulting solution wasstirred at 0° C. for 30 minutes. The reaction mixture was quenched byaddition of a saturated aqueous solution of sodium bicarbonate (100 mL).The mixture was extracted with ethyl acetate (3×150 mL). The combinedorganics were then washed with brine (100 mL), dried over sodiumsulfate, filtered, and concentrated. Purification via silica gelchromatography (Gradient: 0% to 50% ethyl acetate in heptane) affordedthe product as a white solid. Yield: 540 mg, 51%. ¹H NMR (400 MHz,CD₃OD) characteristic peaks: δ 8.13 (br d, J=7.4 Hz, 2H), 7.44-7.57 (m,4H), 7.13 (dd, J=12.1, 8.6 Hz, 1H), 6.05 (dd, J=6.3, 1.0 Hz, 1H),4.58-4.63 (m, 1H), 4.48 (dd, J=7.9, 6.4 Hz, 1H), 4.12-4.15 (m, 1H), 3.85(d, J=11.9 Hz, 1H), 3.63 (s, 3H), 3.20 (br s, 1H), 2.93 (dd, J=13.1, 4.1Hz, 1H), 2.72 (J=13.2, 2.8 Hz, 1H), 1.84-1.90 (m, 1H), 1.71-1.75 (m,1H).

Step 3. Synthesis ofN-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(1,1,3,3-tetramethoxypropan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C44)

To a solution ofN-{(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-[(E)-2-methoxyethenyl]-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl}benzamide(C43) (0.54 g, 1.1 mmol) in dichloromethane (2 mL) at 0° C., was addedtrimethyl orthoformate (0.239 mL, 2.19 mmol) followed by drop-wiseaddition of boron trifluoride-diethyl etherate (0.136 mL, 1.08 mmol),without letting the reaction temperature exceed 3° C. The resultingsolution was allowed to stir at the same temperature for 1.5 hours. Thereaction mixture was diluted with dichloromethane (200 mL) and asaturated aqueous solution of sodium bicarbonate (200 mL). The organiclayer was separated and resulting aqueous layer was extracted withfurther dichloromethane (200 mL). The combined organics were washed withbrine (200 mL), dried over sodium sulfate, filtered and concentrated togive the product (0.65 g) as a white solid, which was taken directly tothe following step. ¹H NMR (400 MHz, CD₃OD) characteristic peaks: δ 8.23(br d, J=7.0 Hz, 2H), 7.41-7.52 (m, 5H), 6.99 (dd, J=1.7, 9.0 Hz, 1H),4.52 (dd, J=17.7, 4.2 Hz, 1H), 4.13 (d, J=12.5 Hz, 1H), 4.04 (d, J=8.4Hz, 1H), 3.79 (d, J=11.9 Hz, 1H), 3.13-3.19 (m, 1H), 2.98 (dd, J=13.1,2.7 Hz, 1H), 2.64 (dd, J=13.1, 1.3 Hz, 1H).

Step 4. Synthesis of(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine(C45)

Methylhydrazine (0.0834 mL, 1.60 mmol) followed by water (2.2 mL) wasadded to a solution ofN-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(1,1,3,3-tetramethoxypropan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C44) (0.65 g, 1.06 mmol) in ethanol (5 mL). Sulfuric acid (0.110 mL,2.07 mmol) was then added in a drop-wise manner to the reaction mixture.The resulting solution was heated to 60° C. for 16 hours. The reactionmixture was partitioned between ethyl acetate (100 mL) and a saturatedaqueous solution of sodium bicarbonate (100 mL). The layers wereseparated and the resulting aqueous layer was further extracted withethyl acetate (3×100 mL). The combined organic layers were then driedover sodium sulfate, filtered and concentrated to give a mixture ofproduct and benzoylated product (0.79 g), which was taken directly tothe following step. LCMS m/z 427.1 [M+H⁺] (product) and m/z 527.1 [M+H⁺](benzoylated product).

Step 5. Synthesis ofN-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C46)

A solution of(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine(C45) (0.79 g, 2.17 mmol) in tetrahydrofuran (10 mL) and methanol (5 mL)was treated with triethylamine (0.488 mL, 3.48 mmol) followed by benzoicanhydride (0.639 g, 2.82 mmol). The resulting homogeneous solution wasallowed to stir at room temperature for 16 hours. The reaction mixturewas partitioned between water (100 mL) and ethyl acetate (100 mL). Thelayers were isolated and resulting aqueous layer was further extractedwith ethyl acetate (2×100 mL). The combined organics were then washedwith water (150 mL), and with brine (150 mL), dried over sodium sulfateand filtered. Purification via silica gel chromatography (Gradient: 30%to 100% ethyl acetate in heptane) afforded the product as an off-whitesolid. Yield 338 mg, 60% over 2 steps. LCMS m/z 531.2 [M+H⁺]. ¹H NMR(400 MHz, CD₃OD) characteristic peaks δ 8.13 (br d, J=6.8 Hz, 2H),7.53-7.62 (m, 3H), 7.45-7.48 (m, 2H), 7.17 (dd, J=12.2, 8.7 Hz, 1H),5.49 (s, 1H), 4.76 (dd, J=11.5, 2.2 Hz, 1H), 4.27 (d, J=12.1 Hz, 1H),4.07-4.12 (m, 1H), 3.96-3.93 (d, J=11.9 Hz, 1H), 3.84 (s, 3H), 2.98 (dd,J=13.0, 4.0 Hz, 1H), 2.79 (dd, J=13.1, 2.7 Hz, 1H), 2.12-2.17 (m, 1H),1.97-2.01 (m, 1H).

Step 6. Synthesis ofN-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C47)

N-[(4aR,6R,8aS)-8a-(5-Bromo-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C46) was converted to the product using the method described forsynthesis ofN-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C37) as in Example 10. The product was obtained as a white solid.Yield: 265 mg, 98%. LCMS m/z 476.2 [M+H⁺]. ¹H NMR (400 MHz, CD₃OD)characteristic peaks: δ 8.11 (br d, J=7.4 Hz, 2H), 7.98 (br s, 1H),7.83-7.85 (m, 1H), 7.64-7.67 (m, 3H), 7.54-7.58 (m, 2H), 7.40-7.53 (m,1H), 4.77 (dd, J=11.4, 2.2 Hz, 1H), 4.25-4.29 (m, 1H), 4.07-4.12 (m,1H), 3.96 (d, J=11.5 Hz, 1H), 3.84 (s, 3H), 2.93-2.97 (m, 1H), 2.80 (dd,J=13.2, 2.6 Hz, 1H), 2.13-2.120 (m, 1H), 1.97-2.01 (m, 1H).

Step 7. Synthesis of3-[(4aR,6R,8aS)-2-amino-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile(12)

1,8-Diazabicycloundec-7-ene (0.298 mL, 1.89 mmol) was added to asolution ofN-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C47) (1.11 g, 2.71 mmol) in methanol (100 mL). The resulting solutionwas heated to 50° C. for 16 hours. The reaction mixture was concentratedunder reduced pressure. Purification via silica gel chromatography(Gradient: 0% to 20% methanol in dichloromethane) afforded the productas an off-white solid. Yield: 79 mg, 38%. LCMS m/z 372.2 [M+H⁺]. ¹H NMR(400 MHz, CD₃OD) δ 7.77 (ddd, J=8.5, 4.5, 2.2 Hz, 1H), 7.69 (dd, J=7.2,2.2 Hz, 1H), 7.60 (s, 1H), 7.47 (s, 1H), 7.36 (dd, J=12.1, 8.6 Hz, 1H),4.71 (dd, J=11.6, 2.2 Hz, 1H), 4.24 (dd, J=11.2, 2.3 Hz, 1H), 3.87 (s,3H), 3.76 (d, J=11.2 Hz, 1H), 3.06-3.11 (m, 1H), 2.89 (dd, J=12.5, 4.1Hz, 1H), 2.76 (dd, J=12.7, 2.7 Hz, 1H), 2.04-2.14 (m, 1H), 1.82-1.87 (m,1H).

Example 133-[(4aR,6R,8aS)-2-Amino-6-cyclopropyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile(13)

Step 1. Synthesis of [1-(2,2-diethoxyethoxyl)but-3-en-1-yl]cyclopropane(C49)

1-Cyclopropylbut-3-en-1-ol (C48, see C. Tahtaoui et al., J. Org. Chem.2010, 75, 3781-3785) (92%, 8.1 g, 66 mmol) was added to a 0° C.suspension of sodium hydride (60% in mineral oil, 8.25 g, 206 mmol) intetrahydrofuran (105 mL). The cooling bath was removed and thesuspension was stirred until the internal temperature reached 21° C. Thereaction mixture was then cooled in an ice bath, and2-bromo-1,1-diethoxyethane (97%, 18.5 mL, 119 mmol) was added drop-wiseat a rate that maintained the internal temperature below 5° C. Afterwarming to room temperature, the reaction mixture was heated to 58° C.for 27 hours. Sodium hydride (60% in mineral oil, 3.3 g, 83 mmol) and2-bromo-1,1-diethoxyethane (97%, 10 mL, 64 mmol) were added again, andthe reaction mixture was heated at mild reflux for 14 hours. It was thencooled to 0° C., slowly quenched with water (100 mL) and extracted withdiethyl ether (3×200 mL). The combined organic layers were dried oversodium sulfate, filtered, and concentrated in vacuo; purification viasilica gel chromatography (Gradient: 0% to 10% ethyl acetate in heptane)afforded the product as a colorless oil. Yield: 12.1 g, 53.0 mmol, 80%.¹H NMR (400 MHz, CDCl₃) δ 5.87-5.98 (m, 1H), 5.05-5.11 (m, 1H),5.00-5.04 (m, 1H), 4.61 (t, J=5.3 Hz, 1H), 3.66-3.75 (m, 3H), 3.54-3.62(m, 2H), 3.47 (dd, J=10.3, 5.5 Hz, 1H), 2.70 (dt, J=8.4, 6.0 Hz, 1H),2.36-2.41 (m, 2H), 1.22 (t, J=7.0 Hz, 3H), 1.22 (t, J=7.0 Hz, 3H),0.80-0.90 (m, 1H), 0.54-0.62 (m, 1H), 0.35-0.50 (m, 2H), 0.07-0.14 (m,1H).

Step 2. Synthesis of [(1-cyclopropylbut-3-en-1-yl)oxy]acetaldehyde (C50)

A mixture of [1-(2,2-diethoxyethoxyl)but-3-en-1-yl]cyclopropane (C49)(2.97 g, 13.0 mmol), aqueous hydrochloric acid (1 M, 39 mL, 39 mmol) andtetrahydrofuran (39 mL) was stirred at room temperature for 12.5 hours,then heated to 40° C. for 3 hours. The reaction mixture was cooled toroom temperature and slowly transferred into a stirring biphasic mixtureof saturated aqueous sodium bicarbonate solution (200 mL) and diethylether (200 mL). The aqueous layer was extracted with diethyl ether(2×100 mL) and the combined organic extracts were dried over sodiumsulfate, filtered, and concentrated in vacuo (900 mbar, 60° C.) toafford the product as a colorless oil (3.63 g), which contained residualdiethyl ether and tetrahydrofuran by ¹H NMR analysis. This material wastaken directly into the following step. ¹H NMR (400 MHz, CDCl₃) δ9.76-9.78 (m, 1H), 5.86-5.98 (m, 1H), 5.04-5.15 (m, 2H), 4.15 (br ABquartet, J_(AB)=17.8 Hz, Δν_(AB)=22.8 Hz, 2H), 2.71 (dt, J=8.8, 5.9 Hz,1H), 2.41-2.47 (m, 2H), 0.81-0.91 (m, 1H), 0.58-0.66 (m, 1H), 0.49-0.57(m, 1H), 0.31-0.38 (m, 1H), 0.08-0.15 (m, 1H).

Step 3. Synthesis of2-[(1-cyclopropylbut-3-en-1-yl)oxy]-N-hydroxyethanimine (C51)

[(1-Cyclopropylbut-3-en-1-yl)oxy]acetaldehyde (C50) (3.63 g from theprevious step, ≦13.0 mmol) was dissolved in a 2:1 mixture of ethanol andwater (39 mL). Sodium acetate (5.32 g, 64.9 mmol) was added; after thereaction mixture had been stirred for 15 minutes, hydroxylaminehydrochloride (98%, 2.76 g, 38.9 mmol) was added. The reaction mixturewas heated to 60° C. for 5 minutes, at which time water (4×1 mL) wasadded until a solution formed. After 1 hour at 60° C., the reactionmixture was cooled, concentrated under reduced pressure to removeethanol, and diluted with saturated aqueous sodium chloride solution(100 mL). The mixture was extracted with diethyl ether (3×100 mL), andthe combined organic layers were dried over sodium sulfate, filtered,and concentrated in vacuo at 22° C. Silica gel chromatography (Gradient:0% to 25% ethyl acetate in heptane) provided the product as a thick,opaque oil. By ¹H NMR analysis, this material consisted of a roughly 1:1mixture of E and Zoxime isomers. Yield: 1.771 g, 10.47 mmol, 81% overtwo steps. ¹H NMR (400 MHz, CDCl₃) δ [7.50 (dd, J=5.7, 5.6 Hz) and6.92-6.99 (m), total 1H], 5.84-5.97 (m, 1H), 5.03-5.15 (m, 2H), {[4.53(dd, half of ABX pattern, J=16.4, 3.5 Hz) and 4.41 (dd, half of ABXpattern, J=16.4, 3.6 Hz)] and [4.27 (dd, half of ABX pattern, J=12.9,5.5 Hz) and 4.16 (dd, half of ABX pattern, J=12.9, 5.8 Hz)], total 2H},2.65-2.74 (m, 1H), 2.37-2.44 (m, 2H), 0.81-0.91 (m, 1H), 0.59-0.68 (m,1H), 0.47-0.56 (m, 1H), 0.35-0.44 (m, 1H), 0.07-0.15 (m, 1H).

Step 4. Synthesis ofrel-(3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole(C52)

An aqueous solution of sodium hypochlorite (6.15% solution, 27.1 mL,22.4 mmol) was added drop-wise over 24 minutes to a solution of2-[(1-cyclopropylbut-3-en-1-yl)oxy]-N-hydroxyethanimine (C51) (1.85 g,10.9 mmol) and triethylamine (0.114 mL, 0.818 mmol) in dichloromethane(64 mL) that was immersed in a room temperature water bath. The rate ofaddition was adjusted to maintain the internal temperature of thereaction between 19.5° C. and 22.8° C. After completion of the addition,the reaction mixture was diluted with water (50 mL) and the aqueouslayer was extracted with dichloromethane (3×50 mL). The combined organiclayers were washed with saturated aqueous sodium chloride solution (50mL), dried over sodium sulfate, filtered, and concentrated in vacuo (300mbar, 40° C.) to provide the product as a pale yellow oil. The indicatedrelative stereochemistry of compound C52 was assigned based on nuclearOverhauser enhancement studies, which revealed an interaction betweenthe methine protons on carbons 3a and 5. Yield: 1.73 g, 10.3 mmol, 94%.GCMS m/z 167 [M⁺]. ¹H NMR (400 MHz, CDCl₃) δ 4.73 (d, J=13.5 Hz, 1H),4.61 (dd, J=10.2, 8.0 Hz, 1H), 4.14 (dd, J=13.5, 1.0 Hz, 1H), 3.80 (dd,J=11.5, 8.0 Hz, 1H), 3.36-3.48 (m, 1H), 2.83 (ddd, J=11.0, 8.0, 1.8 Hz,1H), 2.31 (ddd, J=13.0, 6.5, 1.5 Hz, 1H), 1.64 (ddd, J=12.8, 11.4, 11.3Hz, 1H), 0.89-0.98 (m, 1H), 0.51-0.64 (m, 2H), 0.38-0.45 (m, 1H),0.21-0.28 (m, 1H).

Step 5. Preparation of(3aS,5S)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazoleand(3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole(C53 and C54)

Racemicrel-(3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole(C52) (20 g, 0.12 mol) was separated into its enantiomers usingsupercritical fluid chromatography (Column: ChiralPAK® AS-H, 5 μm;Eluent: 9:1 carbon dioxide/methanol). The second-eluting enantiomerprovided(3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazoleas a pale yellow solid. The indicated absolute stereochemistry wasassigned to compound C54 on the basis of the biological activity of thiscompound's final targets, which proved active (Table 1).

The first-eluting enantiomer provided(3aS,5S)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazoleas a pale yellow solid. Yield: 8.97 g, 0.053 mol, 44%. GCMS m/z 167[M⁺]. ¹H NMR (400 MHz, CDCl₃) δ 4.69 (d, J=13.5 Hz, 1H), 4.57 (ddd,J=10.2, 7.9, 0.7 Hz, 1H), 4.14 (dt, J=13.4, 1.0 Hz, 1H), 3.77 (dd,J=11.8, 7.7 Hz, 1H), 3.39 (qd, J=11.1, 6.7, 1H), 2.81 (ddd, J=10.3, 8.7,1.4 Hz, 1H), 2.28 (ddd, J=13.1, 6.5, 1.6 Hz, 1H), 1.64 (ddd, J=12.8,11.4, 11.3 Hz, 1H), 0.86-0.95 (m, 1H), 0.49-0.61 (m, 2H), 0.36-0.42 (m,1H), 0.19-0.25 (m, 1H).

The second-eluting enantiomer provided(3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazoleas a pale yellow solid. Yield: 8.75 g, 52.3 mmol, 44%. GCMS m/z 167[M⁺]. ¹H NMR (400 MHz, CDCl₃) δ 4.51 (d, J=13.7 Hz, 1H), 4.39 (dd,J=10.3, 8 Hz, 1H), 3.92 (dd, J=13.7, 1.2 Hz, 1H), 3.58 (dd, J=11.7, 8.2Hz, 1H), 3.19 (qd, J=11.1, 6.4 Hz, 1H), 2.61 (ddd, J=11.1, 8, 1.6 Hz,1H), 2.08 (ddd, J=13, 6.5, 1.6 Hz, 1H), 1.38-1.46 (m, 1H), 0.718 (qt,J=8.1, 4.9 Hz, 1H), 0.31-0.42 (m, 2H), 0.17-0.23 (m, 1H), 0.0-0.06 (m,1H).

Step 6. Synthesis of(3aR,5R,7aS)-7a-(5-bromo-2-fluorophenyl)-5-cyclopropylhexahydro-1H-pyrano[3,4-c][1,2]oxazole(C55)

A solution of(3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole(C54) (180 mg, 1.08 mmol) in toluene (7 mL) was cooled to −78° C. Borontrifluoride-diethyl etherate (46.5%, 0.318 mL, 1.18 mmol) was added andthe reaction was stirred at −78° C. for 15 minutes. A solution of4-cyano-1-fluoro-2-bromobenzene (237 mg, 1.18 mmol) in toluene (2 mL)was slowly added and the reaction was stirred for 5 minutes.tert-Butyllithium (1.7 M in toluene, 1.39 mL, 2.37 mmol) was addeddrop-wise and the reaction was allowed to stir at −78° C. for 1.25hours. The reaction was quenched by addition of a saturated aqueoussolution of ammonium chloride (5 mL) and allowed to warm to roomtemperature. The mixture was diluted with water (5 mL) and extractedwith ethyl acetate (2×50 mL). The organics were combined, dried overmagnesium sulfate, filtered and concentrated to give the product, whichwas taken directly to the following step. LCMS m/z 289.2 [M+H⁺].

Step 7. Synthesis of[(2R,4R,5S)-5-amino-5-(5-bromo-2-fluorophenyl)-2-cyclopropyltetrahydro-2H-pyran-4-yl]methanol(C56)

Zinc dust (1.06 g, 16.2 mmol) was added to a solution of(3aR,5R,7aS)-7a-(5-bromo-2-fluorophenyl)-5-cyclopropylhexahydro-1H-pyrano[3,4-c][1,2]oxazole(C55) (311 mg, 1.08 mmol) in acetic acid (56 mL). The reaction mixturewas allowed to stir at room temperature overnight. The reaction wasfiltered through an empty Bakerbond cartridge, eluting with ethylacetate to remove the zinc. The filtrate was concentrated and thenpassed through a 4 g methanol-conditioned MCX cartridge. This was washedwith methanol (4×15 mL), dichloromethane (4×15 mL) and 2 N ammonia inmethanol (40 mL). The filtrate was concentrated in vacuo to give theproduct (225 mg), which was taken directly to the following step. LCMSm/z 291.2 [M+H⁺].

Step 8. Synthesis ofN-{[(3S,4R,6R)-3-(5-bromo-2-fluorophenyl)-6-cyclopropyl-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide(C57)

Benzoyl isothiocyanate (120 mg, 0.74 mmol) was added drop-wise to asolution of[(2R,4R,5S)-5-amino-5-(5-bromo-2-fluorophenyl)-2-cyclopropyltetrahydro-2H-pyran-4-yl]methanol(C56) (from the previous step, 225 mg, ≦50.78 mmol) in dichloromethane(25 mL) at 0° C. The reaction mixture was allowed to stir at 0° C. for1.5 hours, then was warmed to room temperature and stirred overnightbefore concentrating in vacuo. Purification via silica gelchromatography (Gradient: 0% to 100% ethyl acetate in heptane) affordedthe product as a solid. Yield: 127 mg, 26% over 2 steps LCMS m/z 454.3[M+H⁺].

Step 9. Synthesis ofN-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-cyclopropyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C58)

A solution ofN-{[(3S,4R,6R)-3-(5-bromo-2-fluorophenyl)-6-cyclopropyl-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide (C57) (127 mg, 0.28mmol) and pyridine (81 μL, 1.01 mmol) in dichloromethane (12 mL) wascooled to −50° C. Trifluoromethanesulfonic anhydride (94 μL, 0.56 mmol)was added drop-wise to the solution and the mixture was gradually warmedto 0° C. over 90 minutes. The reaction mixture was diluted withdichloromethane (20 mL), washed with water (2×30 mL), dried overmagnesium sulfate, filtered, and concentrated in vacuo. Purification viasilica gel chromatography (Gradient: 0% to 100% ethyl acetate inheptane) afforded the product as a solid. Yield: 83 mg, 68%. LCMS m/z436.2 [M+H⁺].

Step 10. Synthesis of3-[(4aR,6R,8aS)-2-amino-6-cyclopropyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile(13)

Hydrazine monohydrate (0.101 mL, 1.34 mmol) was added to a solution ofN-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-cyclopropyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C58) (83 mg, 0.19 mmol) in ethanol (4 mL). The reaction mixture wasallowed to stir at room temperature overnight and was then concentratedin vacuo. The residue was purified by reverse phase chromatography toprovide the product as a white solid. Yield: 40.3 mg, 64%. Column:Waters XBridge C18, 19×100 mm, 5 μm; Mobile phase A: 0.03% ammoniumhydroxide in water (v/v); Mobile phase B: 0.03% ammonium hydroxide inacetonitrile (v/v); Gradient: 20.0% acetonitrile to 60% B, linear over8.5 minutes; Flow rate: 25 mL/min. LCMS m/z 332.1868 [M+H⁺]. QCretention time: 1.92 minutes (Column: Waters Atlantis dC18, 4.6×50 mm, 5μm; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobilephase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient:5.0% to 95% B, linear over 4.0 minutes; Flow rate: 2 mL/min).

Example 143-[(4aR,6S,8aS)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile(14)

Step 1. Synthesis of4-fluoro-3-[(3aR,5S,7aS)-5-methyltetrahydro-1H-pyrano[3,4-c][1,2]oxazol-7a(7H)-yl]benzonitrile(C59)

To a mixture of 3-bromo-4-fluorobenzonitrile (22.3 g, 112 mmol)dissolved in a 10:1 toluene-tetrahydrofuran mixture (530 mL) cooled to−78° C. was added n-butyllithium (2.5 M in hexanes, 42.5 mL, 106 mmol)drop-wise. The reaction mixture was stirred at −78° C. for 1 hour atwhich point a solution of P2 (7.5 g, 53 mmol) in 10:1toluene-tetrahydrofuran (177 mL) and boron trifluoride-diethyl etheratecomplex (46.5%, 13.3 mL, 50.1 mmol) were simultaneously added drop-wise.The reaction mixture was stirred at −78° C. for 2 hours, at which pointa solution of saturated aqueous ammonium chloride was added. Thereaction mixture was warmed to room temperature and the aqueous wasextracted three times with ethyl acetate. The combined organic layerswere washed with water and with brine, dried over sodium sulfate,filtered and concentrated. Silica gel chromatography (Gradient: 0% to50% ethyl acetate in heptane) provided the product as a yellow oil thatsolidified over time. Yield: 11.4 g, 45.1 mmol, 85%. LCMS m/z 263.3[M+H⁺]. ¹H NMR (400 MHz, CDCl₃), δ 8.34 (dd, J=7.3, 2.2 Hz, 1H), 7.60(ddd, J=8.5, 4.6, 2.3 Hz, 1H), 7.16 (dd, J=11.5, 8.4 Hz, 1H), 4.10 (dd,J=12.5, 2.2 Hz, 1H), 3.80 (br d, J=12.7 Hz, 1H), 3.68-3.77 (m, 2H), 3.51(dd, J=7.2, 5.1 Hz, 1H), 3.08 (dddd, J=11.5, 6.8, 4.9, 1.9 Hz, 1H), 1.88(ddd, J=14.2, 6.9, 2.2 Hz, 1H), 1.41-1.50 (m, 1H), 1.27 (d, J=6.1, 3H).

Step 2. Synthesis of3-[(3S,4R,6S)-3-amino-4-(hydroxymethyl)-6-methyltetrahydro-2H-pyran-3-yl]-4-fluorobenzonitrile(C60)

To a solution of C59 (23.5 g, 89.8 mmol) in glacial acetic acid (428 mL)was added zinc dust (58.7 g, 898 mmol). The reaction mixture was allowedto stir at 40° C. for 16 hours. The reaction mixture was filteredthrough a Celite pad with ethyl acetate (3×500 mL). The combinedfiltrate was washed with 1 N aqueous sodium hydroxide (900 mL). Theorganic layer was removed and the aqueous washed with ethyl acetate(3×250 mL). The combined organics were washed with brine (1×500 mL),dried over sodium sulfate, filtered and concentrated in vacuo to provide10 g of product as a yellow oil. To the aqueous layer from theextraction was added 1 N aqueous sodium hydroxide until a pH of 9 wasachieved. The resulting aqueous was extracted with dichloromethane(3×500 mL) and the combined organics were washed with brine (1×1000 mL),dried over sodium sulfate, filtered and concentrated in vacuo to provide13.5 g of product as a yellow oil. Yield: 23.5 g, 88.9 mmol, 99%. ¹H NMR(400 MHz, CDCl₃), δ 8.12 (dd, J=7.1, 2.1 Hz, 1H), 7.63 (ddd, J=8.4, 4.5,2.2 Hz, 1H), 7.16 (dd, J=11.8, 8.5 Hz, 1H), 4.16 (dd, J=11.3, 2.7 Hz,1H), 3.72 (dqd, J=11.7, 6.1, 2.6 Hz, 1H), 3.44-3.48 (m, 1H), 3.35-3.39(m, 2H), 2.36 (dq, J=12.7, 3.6 Hz, 1H), 1.83-1.93 (m, 1H), 1.71 (ddd,J=14.2, 4.4, 2.7 Hz, 1H), 1.33 (d, J=6.3 Hz, 3H).

Step 3. Synthesis ofN-[(4aR,6S,8aS)-8a-(5-cyano-2-fluorophenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C61)

To C60 (20.47 g, 77.45 mmol) dissolved in dichloromethane (774 mL) wasadded benzoyl isothiocyanate (10.3 mL, 76.7 mmol). The resultingsolution was stirred at room temperature for 18 hours at which pointGhosez's reagent (26.7 mL, 194 mmol) was added. The reaction mixture wasallowed to stir at room temperature for 2 hours at which point saturatedaqueous sodium bicarbonate (500 mL) was added. The aqueous was removedand the organic layer was washed with water (3×500 mL) and with brine(500 mL), dried over sodium sulfate, filtered and concentrated in vacuoto provide a yellow solid. The solids were triturated with ethyl acetate(100 mL) to provide a white solid that was washed with ethyl acetate(2×50 mL) and dried in vacuo. Yield: 23.3 g, 56.9 mmol, 74%. LCMS m/z410.2 [M+H⁺]. ¹H NMR (400 MHz, CD₃OD), δ 8.08-8.15 (m, 2H), 7.79-7.84(m, 2H), 7.54-7.58 (m, 1H), 7.46-7.49 (m, 2H), 7.4 (dd, J=12, 8.5 Hz,1H), 4.11 (dd, J=11.9, 1.8 Hz, 1H), 3.86 (d, J=11.7 Hz, 1H), 3.77-3.85(m, 1H), 3.14-3.21 (m, 1H), 2.91 (dd, J=13.9, 3.1 Hz, 1H), 2.73 (dd,J=13.2, 2.8 Hz, 1H), 1.70-1.83 (m, 2H), 1.26 (d, J=6.1, 3H).

Step 4. Synthesis of3-[(4aR,6S,8aS)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile(14)

To C61 (5.96 g, 14.6 mmol) in methanol (539 mL) was added1,8-diazabicycloundec-7-ene (1.60 mL, 10.1 mmol) and the reactionmixture was heated at 50° C. for 16 hours. Glacial acetic acid (1.48 mL)was added and the reaction mixture was concentrated in vacuo. Theresidue was dissolved with dichloromethane (200 mL) at which pointsaturated aqueous sodium bicarbonate (500 mL) was added. The organiclayer was removed and the aqueous was extracted with dichloromethane(3×100 mL). The organics were combined and washed with brine (250 mL),dried over sodium sulfate, filtered and concentrated on silica gel.Silica gel chromatography (Gradient: 0% to 100% ethyl acetate inheptane) provided the product as a white solid. Yield: 3.25 g, 10.65mmol, 73%. LCMS m/z 306.1 [M+H⁺]. ¹H NMR (400 MHz, CD₃OD), δ 7.74 (ddd,J=8.4, 4.4, 2.2 Hz, 1H), 7.65 (dd, J=7.2, 2.2 Hz, 1H), 7.31 (dd, J=12.1,8.4 Hz, 1H), 4.07 (dd, J=11.1, 2.4 Hz, 1H), 3.7-3.78 (m, 1H), 3.64 (d,J=11.2 Hz, 1H), 2.92 (dtd, J=11.9, 4.3, 2.9 Hz, 1H), 2.80-2.84 (m, 1H),2.67 (dd, J=12.6, 2.8 Hz, 1H), 1.66-1.76 (m, 1H), 1.55 (ddd, J=13.1,4.2, 2.4 Hz, 1H), 1.22 (d, J=6.1 Hz, 3H).

Example 15(4aR,6R,8aS)-6-(Fluoromethyl)-8a-(2-fluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine(15)

Step 1. Synthesis ofN-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C67)

Diethylaminosulfur trifluoride (0.434 mL, 3.28 mmol) was added to amixture of pentanes (20 mL) and dichloromethane (31 mL). To theresulting solution was added C33 (525 mg, 1.10 mmol) in dichloromethane(21 mL; it was necessary to apply mild heat to this mixture to afford asolution, and to use the solution promptly) in a drop-wise manner,whereupon the reaction mixture was allowed to stir at room temperaturefor 16 hours. Saturated aqueous sodium bicarbonate solution (100 mL) wasadded and the aqueous layer was extracted with dichloromethane (3×50mL). The combined organic layers were washed with saturated aqueoussodium chloride solution (100 mL), dried over sodium sulfate, filtered,and concentrated in vacuo; silica gel chromatography (Gradient: 20% to100% ethyl acetate in heptane) provided the product as a white solid.Yield: 166 mg, 0.345 mmol, 31%. LCMS m/z 481.2, 483.2 [M+H⁺]. ¹H NMR(400 MHz, CD₃OD) δ 8.08-8.17 (br m, 2H), 7.52-7.60 (m, 3H), 7.47 (br dd,J=7.7, 7.3, 2H), 7.17 (dd, J=12.2, 8.7 Hz, 1H), 4.34-4.42 and 4.46-4.54(2 m, J_(HF)=47.3 and 47.8 Hz, total 2H), 4.15 (dd, J=11.9, 1.6 Hz, 1H),3.92-4.04 (br m, 1H), 3.92 (d, J=11.9 Hz, 1H), 3.18-3.28 (br m, 1H),2.96 (dd, J=13, 4 Hz, 1H), 2.77 (dd, J=13, 3 Hz, 1H), 1.84-1.96 (m, 1H),1.66-1.73 (m, 1H).

Step 2. Synthesis ofN-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C68)

Conversion of C67 to the product, which was isolated as a light yellowsolid, was carried out using the method described for synthesis of C10in Example 1. Yield: 143 mg, 0.334 mmol, 97%. LCMS m/z 428.2 [M+H⁺]. ¹HNMR (400 MHz, CD₃OD) δ 8.05-8.15 (br m, 2H), 7.79-7.86 (m, 2H), 7.57 (brdd, J=7.4, 7.1 Hz, 1H), 7.49 (br dd, J=7.6, 7.1 Hz, 2H), 7.41 (dd,J=12.1, 8.7 Hz, 1H), 4.35-4.42 and 4.47-4.54 (m, J_(HF)=47.4 and 47.8Hz, total 2H), 4.15 (dd, J=11.8, 1.9 Hz, 1H), 3.94-4.05 (br m, 1H), 3.94(d, J=11.8 Hz, 1H), 3.18-3.28 (br m, 1H), 2.94 (dd, J=13, 4 Hz, 1H),2.77 (dd, J=13, 3 Hz, 1H), 1.85-1.97 (m, 1H), 1.67-1.74 (m, 1H).

Step 3. Synthesis of tert-butyl{3-[(4aR,6R,8aS)-2-(benzoylamino)-6-(fluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzyl}carbamate(C69)

Compound C68 (143 mg, 0.334 mmol) was converted to the product using themethod described for synthesis of C25 in Example 8. In this case,addition of tetrahydrofuran to the initial mixture of C68 and methanolwas required in order to obtain a solution. The product (235 mg) wasobtained as a brown solid, contaminated with unreacted startingmaterial; this mixture was carried directly into the following step.LCMS m/z 532.3 [M+H⁺].

Step 4. Synthesis ofN-[(4aR,6R,8aS)-8a-[5-(aminomethyl)-2-fluorophenyl]-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C70)

Compound C69 (235 mg, from the previous step) was converted to theproduct using the method described for synthesis of C26 in Example 8.The product (100 mg), obtained as a brown solid, was carried directly tothe following step. LCMS m/z 432.3 [M+H⁺].

Step 5. Synthesis ofN-[(4aR,6R,8aS)-6-(fluoromethyl)-8a-(2-fluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C71)

Compound C70 (100 mg, from the previous step) was converted to theproduct using the method described for synthesis of C27 in Example 8,providing the product as a white solid. Yield: 23 mg, 45 μmol, 13% overthree steps. LCMS m/z 514.3 [M+H⁺]. ¹H NMR (400 MHz, CDCl₃) δ 8.23 (d,J=7.3 Hz, 2H), 7.53 (br dd, J=7.2, 7.1 Hz, 1H), 7.46 (br dd, J=7.7, 7.0Hz, 2H), 7.37-7.43 (m, 1H), 7.31 (br dd, J=7.6, 1.7 Hz, 1H), 7.11 (dd,J=12.2, 8.3 Hz, 1H), 4.50 (ddd, J=47.5, 9.8, 6.3 Hz, 1H), 4.42 (ddd,J=46.7, 9.8, 3.8 Hz, 1H), 4.22 (br d, J=12.2 Hz, 1H), 3.96-4.07 (m, 1H),3.84-3.92 (m, 3H), 3.21-3.29 (m, 1H), 3.16 (q, J_(HF)=9.4 Hz, 2H), 3.04(dd, J=13.0, 3.9 Hz, 1H), 2.66 (dd, J=12.9, 2.9 Hz, 1H), 1.94-2.07 (m,1H), 1.63-1.72 (m, 1H).

Step 6. Synthesis of(4aR,6R,8aS)-6-(fluoromethyl)-8a-(2-fluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine(15)

Conversion of C71 to the product was carried out using the methoddescribed for synthesis of 8 in Example 8. The product was obtained as awhite solid. Yield: 17 mg, 42 μmol, 93%. LCMS m/z 410.3 [M+H⁺]. ¹H NMR(400 MHz, CDCl₃) δ 7.25-7.31 (m, 2H), 6.99-7.06 (m, 1H), 4.51 (ddd,J=47.6, 9.7, 6.1 Hz, 1H), 4.42 (ddd, J=47.0, 9.7, 3.8 Hz, 1H), 4.15 (dd,J=11.3, 1.9 Hz, 1H), 3.91-4.02 (m, 1H), 3.86-3.91 (m, 3H), 3.17 (q,J_(HF)=9.4 Hz, 2H), 2.96-3.07 (m, 2H), 2.60-2.67 (m, 1H), 1.80-1.92 (m,1H), 1.52 (ddd, J=13, 4, 2 Hz, 1H).

Example 16rel-(4aR,6R,8aS)-8a-(2-Fluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine(16)

Step 1. Synthesis of tert-butyl{3-[rel-(4aR,6R,8aS)-2-(benzoylamino)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzyl}carbamate(C72)

N-[rel-(4aR,6R,8aS)-8a-(5-Cyano-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide[(+/−)-C47, which may be prepared in the same manner as C47, by usingthe chemistry described in Preparation 1 followed by Examples 10 and 12,but employing racemic 2-[(benzyloxy)methyl]oxirane as starting material](440 mg, 0.925 mmol) was converted to the product using the methoddescribed for synthesis of C25 in Example 8. In this case, preparativethin layer chromatography (Eluent: 1:2 petroleum ether/ethyl acetate)was carried out, affording the product as a yellow solid. Startingmaterial C47 (110 mg) was also recovered. Yield: 200 mg, 0.345 mmol, 37%(50% based on recovered starting material). ¹H NMR (400 MHz, CDCl₃),characteristic peaks: δ 8.24 (br d, J=8 Hz, 2H), 7.49-7.54 (m, 1H), 7.47(s, 1H), 7.44 (br dd, J=8, 7 Hz, 2H), 7.41 (s, 1H), 7.10 (dd, J=12.2,8.5 Hz, 1H), 4.73 (br d, J=11.4 Hz, 1H), 4.22-4.35 (m, 3H), 3.86 (s,3H), 3.83-3.91 (m, 1H), 3.28-3.36 (m, 1H), 3.06 (dd, J=12.7, 4.1 Hz,1H), 2.66 (dd, J=12.7, 2.6 Hz, 1H), 2.23-2.35 (m, 1H), 1.89-1.97 (m,1H), 1.40 (s, 9H).

Step 2. Synthesis ofN-[rel-(4aR,6R,8aS)-8a-[5-(aminomethyl)-2-fluorophenyl]-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C73)

A solution of C72 (185 mg, 0.319 mmol) in methanolic hydrogen chloride(4 N, 6 mL) was stirred at room temperature for 1.5 hours. The reactionmixture was concentrated in vacuo, and the residue was partitionedbetween ethyl acetate (100 mL) and saturated aqueous sodium bicarbonatesolution (10 mL). The organic layer was washed with saturated aqueoussodium chloride solution (10 mL), dried over sodium sulfate, andconcentrated under reduced pressure to provide the product as a brownfoam. Yield: 150 mg, 0.313 mmol, 98%.

Step 3. Synthesis ofN-[rel-(4aR,6R,8aS)-8a-(2-fluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C74)

Compound C73 was converted to the product using the method described forsynthesis of C27 in Example 8; in this case, the concentrated reactionmixture was directly subjected to silica gel chromatography (Gradient:0% to 100% ethyl acetate in petroleum ether), affording the product as ayellow foam. Yield: 95 mg, 0.17 mmol, 60%. LCMS m/z 562.1 [M+H⁺]. ¹H NMR(400 MHz, CDCl₃) δ 8.21-8.28 (m, 2H), 7.48 (s, 1H), 7.42 (s, 1H),7.39-7.56 (m, 4H), 7.30-7.36 (m, 1H), 7.12 (dd, J=12.2, 8.4 Hz, 1H),4.74 (br d, J=11.4 Hz, 1H), 4.33 (d, J=12.2 Hz, 1H), 3.87 (s, 3H),3.84-3.92 (m, 3H), 3.29-3.37 (m, 1H), 3.16 (q, J_(HF)=9.3 Hz, 2H),3.03-3.09 (m, 1H), 2.68 (br d, J=13 Hz, 1H), 2.24-2.35 (m, 1H),1.90-1.97 (m, 1H).

Step 4. Synthesis ofrel-(4aR,6R,8aS)-8a-(2-fluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine(16)

Hydrazine monohydrate (76 mg, 1.52 mmol) was added in one portion to asolution of C74 (95 mg, 0.17 mmol) in ethanol (5 mL), and the reactionmixture was allowed to stir at room temperature for 18 hours. Afterremoval of solvent in vacuo, the residue was purified by preparativethin layer chromatography (Eluent: 10:1 dichloromethane/methanol)followed by silica gel chromatography (Eluent: 10% methanol indichloromethane) to afford the product as a white solid. Yield: 25 mg,55 μmol, 32%. LCMS m/z 458.0 [M+H⁺]. ¹H NMR (400 MHz, CDCl₃) δ 7.48 (s,1H), 7.45 (s, 1H), 7.28-7.34 (m, 2H), 7.05 (dd, J=12, 8 Hz, 1H), 4.70(br d, J=11.4 Hz, 1H), 4.25 (br dd, J=11.4, 1.4 Hz, 1H), 3.88 (s, 3H),3.86-3.95 (m, 3H), 3.11-3.23 (m, 3H), 3.01 (dd, J=12.5, 4.0 Hz, 1H),2.67 (dd, J=12.4, 2.7 Hz, 1H), 2.06-2.17 (m, 1H), 1.78-1.85 (m, 1H).

Example 173-[(4R,4aR,6R,8aS)-2-Amino-4-methyl-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile(17)

Step 1. Synthesis of(3S,3aR,5R,7aS)-5-[(benzyloxy)methyl]-7a-(5-bromo-2-fluorophenyl)-3-methylhexahydro-1H-pyrano[3,4-c][1,2]oxazole(C75)

Boron trifluoride-diethyl etherate (10.3 mL, 83.5 mmol) was added to a−78° C. solution of P3 (10.0 g, 38.3 mmol) in toluene (383 mL) andstirring was continued at −78° C. for 30 minutes. Subsequent addition of4-bromo-1-fluoro-2-iodobenzene (11.6 g, 38.6 mmol) was followed by slowintroduction of n-butyllithium (2.5 M in hexanes, 15.5 mL, 38.8 mmol),at a rate such that the internal reaction temperature did not exceed−73° C. After the reaction mixture had stirred at −78° C. for 90minutes, saturated aqueous ammonium chloride solution (200 mL) wasadded; the resulting mixture was allowed to warm to room temperature,whereupon it was partitioned between ethyl acetate (400 mL) and water(800 mL). The aqueous layer was extracted with ethyl acetate (3×200 mL),and the combined organic layers were washed with saturated aqueoussodium chloride solution (200 mL), dried over sodium sulfate, filtered,and concentrated in vacuo. Silica gel chromatography (Gradient: 10% to70% ethyl acetate in heptane) provided the product as a colorless oilyresidue. Yield: 6.14 g, 14.1 mmol, 37%. LCMS m/z 436.2, 438.2 [M+H⁺]. ¹HNMR (400 MHz, CD₃OD) δ 8.06 (dd, J=7.0, 2.7 Hz, 1H), 7.46 (ddd, J=8.7,4.3, 2.7 Hz, 1H), 7.26-7.38 (m, 5H), 7.06 (dd, J=11.6, 8.7 Hz, 1H), 4.57(AB quartet, J_(AB)=12.1 Hz, Δν_(AB)=1 Hz, 2H), 4.02 (qd, J=6.4, 2.4 Hz,1H), 3.94 (dd, J=12.8, 2.1 Hz, 1H), 3.77 (dd, J=12.8, 1.5 Hz, 1H),3.75-3.82 (m, 1H), 3.57 (dd, half of ABX pattern, J=10.4, 5.4 Hz, 1H),3.54 (dd, half of ABX pattern, J=10.4, 4.4 Hz, 1H), 2.83-2.90 (m, 1H),2.02 (ddd, J=14.0, 7.7, 2.6 Hz, 1H), 1.57-1.68 (m, 1H), 0.77 (d, J=6.4Hz, 3H).

Step 2. Synthesis of(1S)-1-[(2R,4R,5S)-5-amino-2-[(benzyloxy)methyl]-5-(5-bromo-2-fluorophenyl)tetrahydro-2H-pyran-4-yl]ethanol(C76)

Samarium iodide (0.1 M solution in tetrahydrofuran, 800 mL, 80 mmol) wasadded drop-wise to a 0° C. solution of C75 (6.00 g, 13.8 mmol) intetrahydrofuran (140 mL), and the reaction mixture was allowed to stirat room temperature for 24 hours. A saturated aqueous solution of sodiumthiosulfate pentahydrate (500 mL) was added to the reaction mixture,followed by extraction with ethyl acetate (3×250 mL). The combinedorganic layers were washed with saturated aqueous sodium chloridesolution (500 mL), dried over sodium sulfate, filtered, and concentratedin vacuo, affording the product as a yellow oily residue. This was useddirectly in the next step. Yield: 6.00 g, 13.7 mmol, 99%. LCMS m/z438.2, 440.2 [M+H⁺]. ¹H NMR (400 MHz, CD₃OD) δ 7.89 (dd, J=7.1, 2.6 Hz,1H), 7.40 (ddd, J=8.7, 4.1, 2.6 Hz, 1H), 7.26-7.38 (m, 5H), 6.98 (dd,J=12.4, 8.6 Hz, 1H), 4.58 (s, 2H), 3.97 (dd, J=11.3, 2.0 Hz, 1H),3.70-3.77 (m, 1H), 3.61 (dd, half of ABX pattern, J=10.3, 5.8 Hz, 1H),3.57-3.65 (m, 1H), 3.56 (dd, half of ABX pattern, J=10.3, 4.0 Hz, 1H),3.39 (d, J=11.3 Hz, 1H), 2.56-2.63 (m, 1H), 1.58-1.70 (m, 2H), 0.99 (d,J=6.5 Hz, 3H).

Step 3. Synthesis ofN-{[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(5-bromo-2-fluorophenyl)-4-[(1S)-1-hydroxyethyl]tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide(C77)

Compound C76 (from the previous step, 6.00 g, 13.7 mmol) was convertedto the product using the method described for synthesis of C8 inExample 1. A portion of the resulting orange solid (8.22 g, ≦13.7 mmol)was taken on to the following step.

Step 4. Synthesis ofN-[(4R,4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(5-bromo-2-fluorophenyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C78)

1-Chloro-N,N,2-trimethylprop-1-en-1-amine (Ghosez's reagent, 4.62 mL,34.9 mmol) was added in a drop-wise manner to a solution of C77 (fromthe previous step, 7.00 g, ≦11.6 mmol) in dichloromethane (225 mL).After the reaction mixture had stirred at room temperature for 1.5hours, it was partitioned between ethyl acetate (500 mL) and saturatedaqueous sodium bicarbonate solution (1 L). The aqueous layer wasextracted with ethyl acetate (3×250 mL), and the combined organic layerswere washed sequentially with water (2×1 L) and saturated aqueous sodiumchloride solution (500 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. The residue was combined with an identicalreaction product obtained from the same batch of C77 (0.250 g, ≦0.416mmol) and purified via silica gel chromatography (Gradient: 0% to 70%ethyl acetate in heptane), providing the product as a white solid.Yield: 4.80 g, 8.23 mmol, 68% over two steps. LCMS m/z 583.2, 585.2[M+H⁺]. ¹H NMR (400 MHz, CD₃OD) δ 8.12 (d, J=7.4 Hz, 2H), 7.49-7.57 (m,3H), 7.43-7.48 (m, 2H), 7.28-7.33 (m, 2H), 7.17-7.26 (m, 3H), 7.14 (dd,J=12.1, 8.6 Hz, 1H), 4.55 (AB quartet, J_(AB)=11.8 Hz, Δν_(AB)=22.4 Hz,2H), 4.13 (br d, J=12 Hz, 1H), 3.91 (d, J=11.8 Hz, 1H), 3.83-3.9 (m,1H), 3.60 (dd, half of ABX pattern, J=10.7, 5.4 Hz, 1H), 3.57 (dd, halfof ABX pattern, J=10.8, 4.1 Hz, 1H), 3.16-3.26 (br m, 1H), 2.97-3.05 (m,1H), 1.71-1.78 (m, 1H), 1.58-1.69 (m, 1H), 1.23 (d, J=7.0 Hz, 3H).

Step 5. Synthesis ofN-[(4R,4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(hydroxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C79)

Compound C78 was converted to the product using the method described forsynthesis of C33 in Example 10. The product was obtained as a whitesolid. Yield: 3.98 g, 8.07 mmol, 98%. LCMS m/z 493.2, 495.1 [M+H⁺]. ¹HNMR (400 MHz, CD₃OD) δ 8.13 (br d, J=7 Hz, 2H), 7.51-7.59 (m, 3H), 7.47(br dd, J=7.6, 7.3 Hz, 2H), 7.16 (dd, J=12.1, 8.6 Hz, 1H), 4.15 (br d,J=12 Hz, 1H), 3.92 (d, J=11.7 Hz, 1H), 3.70-3.77 (m, 1H), 3.60 (d, J=5.2Hz, 2H), 3.18-3.27 (br m, 1H), 2.99-3.07 (br m, 1H), 1.74-1.81 (m, 1H),1.49-1.61 (m, 1H), 1.26 (d, J=6.9 Hz, 3H).

Step 6. Synthesis of(4R,4aR,6R,8aS)-2-(benzoylamino)-8a-(5-bromo-2-fluorophenyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazine-6-carboxylicacid (C80)

Using the method described for synthesis of C34 in Example 10, C79 (3.98g, 8.07 mmol) was converted to the product, which was obtained as apurple solid (3.73 g). This material exhibited aromatic impurities inthe ¹H NMR, but was carried directly to the following step. LCMS m/z507.1, 509.1 [M+H⁺]. ¹H NMR (400 MHz, CD₃OD), characteristic peaks: δ8.06-8.11 (m, 2H), 7.50-7.56 (m, 2H), 4.37 (dd, J=12.0, 2.5 Hz, 1H),4.14 (br AB quartet, J_(AB)=12.1 Hz, Δν_(AB)=57.5 Hz, 2H), 3.3-3.41 (brm, 1H), 3.15-3.23 (m, 1H), 2.17-2.24 (m, 1H), 1.70-1.81 (m, 1H), 1.33(d, J=7.0 Hz, 3H).

Step 7. Synthesis of methyl(4R,4aR,6R,8aS)-2-(benzoylamino)-8a-(5-bromo-2-fluorophenyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazine-6-carboxylate(C81)

Compound C80 (from the previous step, 3.73 g, <7.35 mmol) was convertedto the product using the method described for synthesis of C35 inExample 10. The product, obtained as a yellow solid (3.50 g), containedaromatic impurities as assessed by ¹H NMR, and was taken directly to thefollowing step. LCMS m/z 521.1, 523.1 [M+H⁺]. ¹H NMR (400 MHz, CD₃OD),characteristic peaks: δ 8.05-8.09 (m, 2H), 7.69-7.74 (m, 1H), 7.57-7.62(m, 2H), 4.47 (dd, J=12, 3 Hz, 1H), 4.21 (br AB quartet, J_(AB)=12.5 Hz,Δν_(AB)=25 Hz, 2H), 3.78 (s, 3H), 3.51-3.61 (br m, 1H), 2.21-2.27 (m,1H), 1.72-1.83 (m, 1H), 1.41 (d, J=7.0 Hz, 3H).

Step 8. Synthesis ofN-[(4R,4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-4-methyl-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C82)

Compound C81 (from the previous step, 3.50 g, <6.71 mmol) was convertedto the product using the chemistry described for synthesis of C36 inExample 10. The product was isolated as a white solid. Yield: 2.30 g,4.22 mmol, 52% over 3 steps. LCMS m/z 544.2, 546.1 [M+H⁺]. ¹H NMR (400MHz, CD₃OD) δ 8.06-8.16 (m, 2H), 7.53-7.60 (m, 3H), 7.48 (br dd, J=7.6,7.4 Hz, 2H), 7.17 (dd, J=12.1, 8.6 Hz, 1H), 6.30 (s, 1H), 4.94 (br dd,J=12, 2 Hz, 1H), 4.32 (br d, J=11.7 Hz, 1H), 4.02 (d, J=11.7 Hz, 1H),3.12-3.29 (br m, 2H), 2.26 (s, 3H), 2.13 (br d, J=13 Hz, 1H), 1.86-1.98(m, 1H), 1.28 (d, J=6.9 Hz, 3H).

Step 9. Synthesis ofN-[(4R,4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-4-methyl-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C83)

Using the method described for synthesis of C37 in Example 10, C82 wasconverted to the product, which was obtained as an off-white solid.Yield: 18 mg, 37 μmol, 37%. LCMS m/z 491.1 [M+H⁺]. ¹H NMR (400 MHz,CD₃OD) δ 8.08 (br d, J=7 Hz, 2H), 7.80-7.87 (m, 2H), 7.54-7.60 (m, 1H),7.49 (br dd, J=7.7, 7.2 Hz, 2H), 7.41 (dd, J=12.1, 8.8 Hz, 1H),6.29-6.30 (m, 1H), 4.94 (dd, J=11.7, 2.4 Hz, 1H), 4.31 (dd, J=11.6, 1.6Hz, 1H), 4.03 (d, J=11.6 Hz, 1H), 3.12-3.24 (br m, 2H), 2.26 (br s, 3H),2.10-2.17 (m, 1H), 1.86-1.98 (m, 1H), 1.28 (d, J=6.8 Hz, 3H).

Step 10. Synthesis of3-[(4R,4aR,6R,8aS)-2-amino-4-methyl-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile(17)

Compound C83 was converted to the product using the method described forsynthesis of 12 in Example 12. In this case, silica gel chromatographicpurification was carried out using a gradient of 0% to 100% ethylacetate in heptane. The product was isolated as a white solid. Yield:24.3 mg, 62.9 μmol, 69%. LCMS m/z 387.1 [M+H⁺]. ¹H NMR (400 MHz, CD₃OD)δ 7.78 (ddd, J=8.5, 4.4, 2.2 Hz, 1H), 7.67 (dd, J=7.2, 2.1 Hz, 1H), 7.36(dd, J=12.1, 8.5 Hz, 1H), 6.26 (br s, 1H), 4.88 (dd, J=11.8, 2.5 Hz, 1H,assumed; partially obscured by water peak), 4.28 (dd, J=11.2, 2.1 Hz,1H), 3.84 (d, J=11.2 Hz, 1H), 3.08-3.14 (m, 1H), 2.94-3.00 (m, 1H), 2.28(br s, 3H), 1.96-2.03 (m, 1H), 1.77-1.88 (m, 1H), 1.22 (d, J=6.9 Hz,3H).

Example 18(4aR*,6R*,8aS*)-8a-[2-Fluoro-5-({[(2R)-1-methoxypropan-2-yl]amino}methyl)phenyl]-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine(18)

Step 1. Synthesis of methyl3-[rel-(4aR,6R,8aS)-2-(benzoylamino)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzoate(C84)

To a mixture ofN-[rel-(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide[(+/−)-C46, which may be prepared in the same manner as C46, by usingthe chemistry described in Preparation 1 followed by Examples 10 and 12,but employing racemic 2-[(benzyloxy)methyl]oxirane as starting material](1.0 g, 1.9 mmol) and triethylamine (580 mg, 5.73 mmol) in methanol (20mL) and 1-methylpyrrolidin-2-one (10 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (140 mg,0.19 mmol) in one portion at room temperature. The reaction mixture wasstirred under carbon monoxide (2.5 MPa) at 120° C. for 18 hours,whereupon it was concentrated in vacuo to remove methanol, andpartitioned between water (500 mL) and ethyl acetate (500 mL). Theorganic layer was washed with saturated aqueous sodium chloride solution(2×400 mL), dried over sodium sulfate, filtered, and concentrated underreduced pressure. Silica gel chromatography (Eluent: ethyl acetate)afforded the product as a red solid. Yield: 570 mg, 1.12 mmol, 59%. LCMSm/z 509.1 [M+H⁺].

Step 2. Synthesis ofN-[rel-(4aR,6R,8aS)-8a-[2-fluoro-5-(hydroxymethyl)phenyl]-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C85)

Lithium aluminum hydride (213 mg, 5.61 mmol) was added in one portion toa 0° C. solution of C84 (570 mg, 1.12 mmol) in tetrahydrofuran (50 mL),and the reaction mixture was stirred at room temperature for 1 hour. Itwas then cooled to 0° C., quenched with acetic acid (5 mL), andpartitioned between ethyl acetate (20 mL) and water (20 mL). The organiclayer was washed with saturated aqueous sodium chloride solution (50mL), dried over sodium sulfate, filtered, and concentrated in vacuo toprovide the product (560 mg) as a red foam, which was used directly inthe next step. LCMS m/z 481.1 [M+H⁺].

Step 3. Synthesis ofN-[rel-(4aR,6R,8aS)-8a-(2-fluoro-5-formylphenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C86)

A solution of C85 (560 mg from the previous step, ≦1.12 mmol) andpyridinium chlorochromate (484 mg, 2.24 mmol) in dichloromethane (100mL) was stirred at room temperature for 18 hours. After concentration ofthe reaction mixture in vacuo, purification via chromatography on silicagel afforded the product as a dark solid. Yield: 400 mg, 0.836 mmol, 75%over two steps. ¹H NMR (400 MHz, CDCl₃), characteristic peaks: δ 9.97(s, 1H), 8.21 (br d, J=7 Hz, 2H), 4.75 (br d, J=11.3 Hz, 1H), 4.32 (brd, J=11.5 Hz, 1H), 3.87 (s, 3H), 3.27-3.37 (m, 1H), 2.72 (br d, J=12.3Hz, 1H).

Step 4. Synthesis ofN-[(4aR*,6R*,8aS*)-8a-[2-fluoro-5-({[(2R)-1-methoxypropan-2-yl]amino}methyl)phenyl]-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C87)

Sodium acetate (237 mg, 2.89 mmol) and (2R)-1-methoxypropan-2-aminehydrochloride (121 mg, 0.963 mmol) were added to a solution of C86 (228mg, 0.476 mmol) in anhydrous ethanol (50 mL), and the reaction mixturewas stirred at reflux for 2 hours. Solvent was then removed in vacuo andthe residue was dissolved in anhydrous methanol (100 mL), treated withsodium borohydride (36.5 mg, 0.965 mmol) in one portion, and stirred atreflux for 1 hour. The reaction mixture was concentrated under reducedpressure; purification by preparative thin layer chromatography (Eluent:4:1 dichloromethane/methanol) provided the product as a gray solidYield: 180 mg, 0.326 mmol, 68%.

Step 5. Synthesis of(4aR*,6R*,8aS*)-8a-[2-fluoro-5-({[(2R)-1-methoxypropan-2-yl]amino}methyl)phenyl]-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine(18)

Compound C87 was converted to the product according to the methoddescribed for synthesis of 13 in Example 13. In this case, reversedphase HPLC (Column: Phenomenex Gemini C18, 8 μm; Mobile phase A: aqueousammonia, pH 10; Mobile phase B: acetonitrile; Gradient: 30% to 50% B)afforded the product as a white gum. By ¹H NMR analysis, this was judgedto consist of a mixture of the expected diastereomers. Yield: 37 mg, 83μmol, 25%. LCMS m/z 448.3 [M+H⁺]. ¹H NMR (400 MHz, DMSO-d₆),characteristic peaks: δ 7.60 (s, 1H), 7.33 (s, 1H), 7.24-7.32 (m, 2H),7.12 (dd, J=12, 8 Hz, 1H), 6.14 (br s, 2H), 4.55 (d, J=11.0 Hz, 1H),4.46 (br s, 1H), 4.06 (d, J=11 Hz, 1H), 3.79 (s, 3H), 3.58-3.75 (m, 3H),3.21 and 3.22 (2 s, total 3H), 2.80-2.88 (m, 1H), 2.63-2.79 (m, 3H),1.85-1.98 (m, 1H), 1.71-1.80 (m, 1H), 0.96 (d, J=6.3 Hz, 3H).

Example 19(4S,4aR,6S,8aS)-4-(Fluoromethyl)-8a-(2-fluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine(19)

Step 1. Synthesis of2-{[(5S)-5-(2,2-diethoxyethoxyl)hex-2-yn-1-yl]oxy}tetrahydro-2H-pyran(C88)

Sodium hydride (60% in mineral oil, 9.8 g, 240 mmol) was addedportion-wise to a 0° C. solution of(2S)-6-(tetrahydro-2H-pyran-2-yloxy)hex-4-yn-2-ol (synthesized asdescribed by G. V. M. Sharma and K. Veera Babu, Tetrahedron: Asymmetry2007, 18, 2175-2184) (27.0 g, 136 mmol) in tetrahydrofuran (130 mL), ata rate such that the reaction temperature remained below 5° C. After 5minutes, the cooling bath was removed and the reaction mixture wasallowed to stir at room temperature for 3.5 hours, whereupon it wasagain cooled to 0° C. A solution of 1,1-diethoxy-2-iodoethane (49.9 g,204 mmol) in tetrahydrofuran (5 mL) was added drop-wise over 30 minutes,at a rate that maintained the reaction temperature below 10° C. Afterremoval of the cooling bath, the reaction mixture was stirred at roomtemperature for 30 minutes, and then placed in a 50° C. oil bath for 90minutes, at which time additional 1,1-diethoxy-2-iodoethane (3.3 g, 14mmol) was added, as a solution in tetrahydrofuran (5 mL). Heating wascontinued for 1 hour, at which time the reaction mixture was cooled inan ice bath and quenched with a mixture of saturated aqueous ammoniumchloride solution (210 mL) and saturated aqueous sodium chloridesolution (210 mL). The resulting mixture was extracted with tert-butylmethyl ether (3×200 mL), and the combined organic layers were washedwith saturated aqueous sodium chloride solution, dried over sodiumsulfate, filtered, and concentrated in vacuo. Silica gel chromatography(Gradient: 0% to 50% ethyl acetate in hexanes) afforded the product as ayellow oil. Yield: 22.8 g, 72.5 mmol, 53%. ¹H NMR (500 MHz, CDCl₃),characteristic peaks: δ 4.80 (t, J=3.5 Hz, 1H), 4.59 (t, J=5.2 Hz, 1H),4.28 (dt, half of ABX₂ pattern, J=15.3, 2.1 Hz, 1H), 4.20 (dt, half ofABX₂ pattern, J=15.3, 2.1 Hz, 1H), 3.81-3.87 (m, 1H), 2.48-2.56 (m, 1H),2.28-2.36 (m, 1H), 1.78-1.88 (m, 1H), 1.69-1.77 (m, 1H), 1.25 (d, J=6.1Hz, 3H), 1.22 (t, J=7.1 Hz, 6H).

Step 2. Synthesis of (5S)-5-(2,2-diethoxyethoxyl)hex-2-yn-1-ol (C89)

Benzenesulfonic acid (1.62 g, 10.2 mmol) was added in one portion to a0° C. solution of C88 (32.2 g, 102 mmol) in absolute ethanol (250 mL).The reaction mixture was stirred under ice cooling for 2 hours, then atroom temperature for 18 hours, whereupon it was poured into stirringsaturated aqueous sodium bicarbonate solution (400 mL). Saturatedaqueous sodium chloride solution (200 mL) was added, the aqueous layerwas saturated via addition of solid sodium chloride, and the mixture wasextracted with tert-butyl methyl ether (400 mL, then 3×200 mL). Thecombined organic layers were washed with saturated aqueous sodiumchloride solution, dried over sodium sulfate, filtered, and concentratedin vacuo, providing the product as a yellow oil. Yield: 23.2 g, 101mmol, 99%. ¹H NMR (500 MHz, CDCl₃) δ 4.61 (t, J=5.2 Hz, 1H), 4.24 (dt,J=5.8, 2.2 Hz, 2H), 3.49-3.74 (m, 7H), 2.45-2.53 (m, 1H), 2.34 (ddt,J=16.6, 6.9, 2.2 Hz, 1H), 1.67 (t, J=6.0 Hz, 1H), 1.25 (d, J=6.2 Hz,3H), 1.22 (t, J=7.0 Hz, 6H).

Step 3. Synthesis of (2E,5S)-5-(2,2-diethoxyethoxyl)hex-2-en-1-ol (C90)

A solution of C89 (36.8 g, 160 mmol) in tetrahydrofuran (360 mL) wascooled in an ice bath. A solution of lithium aluminum hydride intetrahydrofuran (1.0 M, 288 mL, 288 mmol) was added drop-wise over 35minutes, at a rate that kept the internal reaction temperature below 7°C. The cooling bath was removed, and the reaction mixture was allowed towarm to room temperature and stir for 4 hours, whereupon it was cooledin an ice bath and treated sequentially with water (68 mL), 6 M aqueoussodium hydroxide solution (34 mL), and water (55 mL). tert-Butyl methylether (600 mL) was added, and the mixture was stirred for 20 minutes andfiltered through diatomaceous earth; the filter pad was rinsed threetimes with tert-butyl methyl ether. The combined filtrates wereconcentrated in vacuo and purified by silica gel chromatography(Gradient: 0% to 50% ethyl acetate in hexanes) to provide the product asa light yellow oil. Yield: 29.0 g, 125 mmol, 78%. ¹H NMR (500 MHz,CDCl₃) δ 5.63-5.79 (m, 2H), 4.59 (t, J=5.3 Hz, 1H), 4.06-4.13 (m, 2H),3.66-3.73 (m, 2H), 3.49-3.61 (m, 4H), 3.44 (dd, half of ABX pattern,J=10.4, 5.4 Hz, 1H), 2.27-2.34 (m, 1H), 2.15-2.22 (m, 1H), 1.34 (t,J=5.8 Hz, 1H), 1.22 (t, J=7.1 Hz, 6H), 1.15 (d, J=6.2 Hz, 3H).

Step 4. Synthesis of(2E,5S)-5-{[(2Z)-2-(hydroxyimino)ethyl]oxy}hex-2-en-1-ol (C91)

Hydroxylamine hydrochloride (12.5 g, 180 mmol) was added to a solutionof C90 (29.0 g, 125 mmol) in ethanol (360 mL) and water (72 mL), and thereaction mixture was placed in a 70° C. oil bath for 3.5 hours. Afterthe reaction mixture had cooled to room temperature, sodium acetate(20.5 g, 250 mmol) was added, and stirring was continued for 20 minutes.Solvent was removed in vacuo, and the aqueous residue was saturated viaaddition of solid sodium chloride, then extracted six times withdichloromethane. The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo, providing the product as ayellow oil. This material was assigned as a mixture of geometric isomersaround the oxime, from examination of its ¹H NMR spectrum. Yield: 18.1g, 104 mmol, 83%. ¹H NMR (500 MHz, CDCl₃) 6 [7.48 (t, J=5.6 Hz) and6.84-6.95 (m), total 1H], 5.59-5.82 (m, 2H), 4.25-4.41 (m, 1H),4.03-4.17 (m, 3H), 3.47-3.60 (m, 1H), 2.27-2.36 (m, 1H), 2.17-2.27 (m,1H), [1.18 (d, J=6.0 Hz) and 1.17 (d, J=6.1 Hz), total 3H].

Step 5. Synthesis of[(3R,3aR,5S)-5-methyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazol-3-yl]methanol(C92)

Saturated aqueous sodium chloride solution (50 mL) was added to asolution of C91 (18.5 g, 107 mmol) in dichloromethane (520 mL). The pHof the aqueous layer was adjusted to 9 through drop-wise addition ofaqueous 6 M sodium hydroxide solution, and an aqueous solution of sodiumhypochlorite (6%, 140 mL, 113 mmol) was then added drop-wise over 40minutes; after 1.5 hours, the pH was again adjusted to 9, and additionalsodium hypochlorite (6%, 140 mL, 113 mmol) was added drop-wise over 20minutes. After 1 hour, the aqueous layer was saturated with solid sodiumchloride and extracted with dichloromethane (6×125 mL), and the combinedorganic layers were dried over sodium sulfate, filtered, concentrated invacuo, and purified via silica gel chromatography (Gradient: 0% to 65%ethyl acetate in hexanes). The product was isolated as a light yellowoil. Yield: 14.0 g, 81.8 mmol, 76%. ¹H NMR (500 MHz, CDCl₃) δ 4.63 (d,J=13.4 Hz, 1H), 4.24 (ddd, J=10.3, 3.2, 3.2 Hz, 1H), 4.17 (dd, J=13.4,1.2 Hz, 1H), 3.99 (ddd, J=12.4, 4.7, 3.0 Hz, 1H), 3.71 (ddd, J=12.4,8.7, 3.5 Hz, 1H), 3.58-3.66 (m, 1H), 3.37-3.45 (m, 1H), 2.10 (ddd,J=12.8, 6.6, 1.6 Hz, 1H), 1.80 (dd, J=8.6, 4.7 Hz, 1H), 1.48-1.56 (m,1H), 1.26 (d, J=6.2 Hz, 3H).

Step 6. Synthesis of[(3R,3aR,5S)-5-methyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazol-3-yl]methyl4-methylbenzenesulfonate (C93)

A solution of C92 (11.9 g, 69.5 mmol) in pyridine (25 mL) was addeddrop-wise over 15 minutes to a 0° C. solution of p-toluenesulfonylchloride (21.2 g, 111 mmol) in pyridine (35 mL), and the reactionmixture was allowed to stir for 18 hours while the cooling bath warmedto room temperature. Solvent was removed in vacuo, and the residue wasdiluted with water (200 mL) and extracted with ethyl acetate (4×120 mL).The combined organic layers were washed sequentially with aqueoushydrochloric acid (1 M, 180 mL), saturated aqueous sodium bicarbonatesolution (180 mL), and water (2×100 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure. The resulting solidwas triturated with tert-butyl methyl ether and washed twice withtert-butyl methyl ether to afford the product as an off-white solid.Yield: 17.4 g, 53.5 mmol, 77%. ¹H NMR (500 MHz, CDCl₃) δ 7.80 (br d, J=8Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 4.60 (d, J=13.3 Hz, 1H), 4.22-4.33 (m,2H), 4.18 (dd, J=10.6, 5.3 Hz, 1H), 4.14 (dd, J=13.3, 1.1 Hz, 1H),3.56-3.64 (m, 1H), 3.27-3.36 (m, 1H), 2.46 (s, 3H), 2.11-2.17 (m, 1H),1.45-1.53 (m, 1H), 1.25 (d, J=6.2 Hz, 3H).

Step 7. Synthesis of(3R,3aR,5S)-3-(fluoromethyl)-5-methyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole(C94)

Compound C93 (24.1 g, 74.1 mmol) was dissolved in a solution oftetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 148 mL, 148mmol), and the reaction mixture was heated at 80° C. for 22 hours. Aftercooling to room temperature, the reaction mixture was concentrated invacuo and purified via silica gel chromatography (Gradient: 0% to 35%ethyl acetate in hexanes), providing the product as a light yellow oil.Yield: 9.93 g, 57.3 mmol, 77%. ¹H NMR (500 MHz, CDCl₃) δ 4.65 (ddd,J=47.4, 10.3, 3.9 Hz, 1H), 4.65 (d, J=13.4 Hz, 1H), 4.59 (ddd, J=46.6,10.2, 4.1 Hz, 1H), 4.29-4.39 (m, 1H), 4.18 (dd, J=13.3, 1.2 Hz, 1H),3.59-3.68 (m, 1H), 3.30-3.41 (m, 1H), 2.14 (ddd, J=12.8, 6.5, 1.6 Hz,1H), 1.50-1.60 (m, 1H), 1.27 (d, J=6.2 Hz, 3H).

Step 8. Synthesis of(3R,3aR,5S,7aS)-3-(fluoromethyl)-7a-(2-fluorophenyl)-5-methylhexahydro-1H-pyrano[3,4-c][1,2]oxazole(C95)

A solution of 1-fluoro-2-iodobenzene (9.9 mL, 85 mmol) in a 10:1 mixtureof toluene and tetrahydrofuran was cooled to −73° C. and treated in adrop-wise manner with boron trifluoride-diethyl etherate (10.2 mL, 82.6mmol), at a rate that kept the internal reaction temperature below −70°C. n-Butyllithium (2.5 M solution in hexanes, 32.3 mL, 80.8 mmol) wasthen added drop-wise over 45 minutes, while maintaining the internalreaction temperature below −72° C. After 30 minutes, a solution of C94(7.00 g, 40.4 mmol) in a 10:1 mixture of toluene and tetrahydrofuran (atotal of 220 mL of this solvent mixture was used for the reaction) wasadded drop-wise over 20 minutes, at a rate that kept the internalreaction temperature below −71° C. After the reaction mixture hadstirred at −70° C. for 40 minutes, it was poured into saturated aqueousammonium chloride solution (200 mL), stirred for 20 minutes, and thenextracted three times with ethyl acetate. The combined organic layerswere washed with saturated aqueous sodium chloride solution, dried oversodium sulfate, filtered, and concentrated in vacuo. Silica gelchromatography (Gradient: 0% to 20% ethyl acetate in hexanes) affordedthe product as a viscous yellow oil. Yield: 10.8 g, 40.1 mmol, 99%. ¹HNMR (500 MHz, CDCl₃) δ 7.94 (ddd, J=8.1, 8.0, 1.8 Hz, 1H), 7.27-7.32 (m,1H), 7.17 (ddd, J=7.7, 7.5, 1.2 Hz, 1H), 7.04 (ddd, J=12.1, 8.2, 1.1 Hz,1H), 4.09-4.18 (m, 1H), 4.04 (dd, J=12.9, 1.9 Hz, 1H), 3.56-3.85 (m,4H), 3.13-3.20 (m, 1H), 2.05 (ddd, J=14.2, 7.5, 1.9 Hz, 1H), 1.46-1.57(m, 1H), 1.27 (d, J=6.2 Hz, 3H).

Step 9. Synthesis of(1R)-1-[(2S,4R,5S)-5-amino-5-(2-fluorophenyl)-2-methyltetrahydro-2H-pyran-4-yl]-2-fluoroethanol(C96)

Zinc dust (34.4 g, 52.6 mmol) was added to a solution of C95 (10.8 g,40.1 mmol) in acetic acid (150 mL). After 16 hours at room temperature,the reaction mixture was filtered through diatomaceous earth; the filterpad was washed three times with ethyl acetate, and the combinedfiltrates were adjusted to pH 8 with aqueous sodium bicarbonatesolution. The aqueous layer was then extracted three times with ethylacetate, and the combined organic layers were dried over sodium sulfate,filtered, and concentrated in vacuo to provide the product as a tansyrup (11.0 g), which was taken directly to the following step. ¹H NMR(500 MHz, CDCl₃) δ 7.59 (ddd, J=8.0, 8.0, 1.7 Hz, 1H), 7.30-7.37 (m,1H), 7.21 (ddd, J=7.6, 7.6, 1.3 Hz, 1H), 7.08 (ddd, J=12.9, 8.2, 1.2 Hz,1H), 4.16 (dd, J=11.5, 1.6 Hz, 1H), 3.56-3.86 (m, 4H), 3.24 (d, J=11.5Hz, 1H), 2.70-2.76 (m, 1H), 1.84-1.94 (m, 1H), 1.68 (ddd, J=14.1, 4.5,2.6 Hz, 1H), 1.32 (d, J=6.1 Hz, 3H).

Step 10. Synthesis ofN-{[(3S,4R,6S)-4-[(1R)-2-fluoro-1-hydroxyethyl]-3-(2-fluorophenyl)-6-methyltetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide(C97)

Benzoyl isothiocyanate (7.9 g, 48 mmol) was added to a solution of C96(from the previous step, 11.0 g, ≦40.1 mmol) in tetrahydrofuran (165mL), and the reaction mixture was stirred at room temperature for 15hours. After removal of solvent under reduced pressure, silica gelchromatography (Gradient: 0% to 30% ethyl acetate in hexanes) providedthe product as a foamy, light yellow solid (17.5 g), which was takendirectly to the following step

Step 11. Synthesis ofN-[(4S,4aR,6S,8aS)-4-(fluoromethyl)-8a-(2-fluorophenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C98)

To a solution of C97 (from the previous step, 17.5 g, ≦40.1 mmol) in1,2-dichloroethane (250 mL) was added methoxybenzene (13.2 mL, 121mmol), followed by trifluoromethanesulfonic acid (10.7 mL, 121 mmol).The reaction mixture was heated at 60° C. for 2.5 hours, then cooled to0° C. and basified to pH 9 with saturated aqueous sodium carbonatesolution. The aqueous layer was extracted three times withdichloromethane, and the combined organic layers were washed withsaturated aqueous sodium chloride solution, dried over sodium sulfate,filtered, and concentrated in vacuo. Silica gel chromatography(Gradient: 0% to 35% ethyl acetate in hexanes) provided the product as awhite foamy solid. Yield: 11.0 g, 26.4 mmol, 66% over three steps. LCMSm/z 417.2 [M+H]+. ¹H NMR (500 MHz, CDCl₃) δ 12.12 (br s, 1H), 8.24 (brs, 2H), 7.34-7.54 (m, 5H), 7.20 (dd, J=7.6, 7.5 Hz, 1H), 7.12 (dd,J=12.6, 8.2 Hz, 1H), 4.58 (ddd, J=46.8, 9.4, 7.7 Hz, 1H), 4.42 (ddd,J=46.3, 9.5, 6.6 Hz, 1H), 4.22 (d, J=11.9 Hz, 1H), 3.81 (d, J=12.0 Hz,1H), 3.75-3.85 (m, 1H), 3.47-3.57 (br m, 1H), 3.26-3.35 (br m, 1H),1.61-1.75 (m, 2H), 1.29 (d, J=6.2 Hz, 3H).

Step 12. Synthesis of(4S,4aR,6S,8aS)-4-(fluoromethyl)-8a-(2-fluorophenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine(C99)

To a solution of C98 (10.9 g, 26.2 mmol) in ethanol (470 mL) were addedmethoxylamine hydrochloride (21.9 g, 262 mmol) and pyridine (21.2 mL,262 mmol). The reaction mixture was heated at 50° C. for 4 hours,whereupon it was cooled to room temperature and concentrated in vacuo.The residue was dissolved in water and neutralized to pH 7-8 with solidsodium bicarbonate. After removal of water under reduced pressure, theresidue was purified via silica gel chromatography (Gradient: 0% to 100%ethyl acetate in hexanes) to provide the product as a white foamy solid.Yield: 6.69 g, 21.4 mmol, 82%. ¹H NMR (500 MHz, CDCl₃) δ 7.34 (ddd,J=8.0, 8.0, 1.8 Hz, 1H), 7.24-7.29 (m, 1H, assumed; partially obscuredby solvent peak), 7.13 (ddd, J=7.7, 7.5, 1.2 Hz, 1H), 7.04 (ddd, J=12.8,8.2, 1.2 Hz, 1H), 4.55 (ddd, J=46.8, 9.4, 6.9 Hz, 1H), 4.35 (ddd,J=46.7, 9.4, 7.0 Hz, 1H), 4.16 (dd, J=11.0, 2.3 Hz, 1H), 3.82 (d, J=11.0Hz, 1H), 3.70-3.77 (m, 1H), 3.43-3.51 (m, 1H), 3.04 (ddd, J=12.0, 4.0,3.9 Hz, 1H), 1.41-1.6 (m, 2H, assumed; partially obscured by waterpeak), 1.27 (d, J=6.2 Hz, 3H).

Step 13. Synthesis of(4S,4aR,6S,8aS)-8a-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine(C100)

Compound C99 (500 mg, 1.60 mmol) was cooled in an ice bath, then treatedwith trifluoroacetic acid (3.1 mL) while keeping the internal reactiontemperature below 30° C. Sulfuric acid (0.51 mL) was added drop-wise ata rate that maintained the internal reaction temperature below 7° C.,and then N-bromosuccinimide (313 mg, 1.76 mmol) was introduced inportions, while keeping the internal temperature below 10° C. Thereaction mixture was warmed to room temperature and subsequently placedin an oil bath preheated to 55° C. After 30 minutes, it was cooled toroom temperature and poured into a cold aqueous solution of sodiumhydroxide [prepared with 1.28 g (32.0 mmol) of sodium hydroxide]. Afterthree extractions of the mixture with ethyl acetate, the combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. The resulting solid was suspended in aqueoussodium hydroxide solution (2 M, 20 mL) and stirred for 4 hours. Thesolid was collected via filtration and washed three times with water toafford the product as an off-white solid. Yield: 527 mg, 1.35 mmol, 84%.¹H NMR (500 MHz, CDCl₃), characteristic peaks: δ 7.43 (dd, J=7.0, 2.6Hz, 1H), 7.37-7.41 (m, 1H), 6.94 (dd, J=11.9, 8.6 Hz, 1H), 4.55 (ddd,J=46.8, 9.4, 7.0 Hz, 1H), 4.36 (ddd, J=46.6, 9.3, 7.0 Hz, 1H), 4.08 (dd,J=11.1, 2.4 Hz, 1H), 3.79-3.86 (m, 1H), 3.67-3.76 (m, 1H), 3.44-3.53 (m,1H), 3.00-3.08 (m, 1H), 1.27 (d, J=6.2 Hz, 3H).

Step 14. Synthesis of tert-butyl[(4S,4aR,6S,8aS)-8a-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]carbamate(C101)

A solution of di-tert-butyl dicarbonate (589 mg, 2.70 mmol) indichloromethane (2 mL) was added to a solution of C100 (527 mg, 1.35mmol) in dichloromethane (2 mL), and the reaction mixture was stirred atroom temperature for 27 hours. Silica gel chromatography (Gradient: 0%to 35% ethyl acetate in hexanes) provided the product as a white solid.Yield: 624 mg, 1.27 mmol, 94%. ¹H NMR (500 MHz, CDCl₃), characteristicpeaks: δ 7.40-7.45 (br m, 1H), 7.32-7.39 (br m, 1H), 6.97 (dd, J=11.9,8.7 Hz, 1H), 4.53 (ddd, J=47.0, 9.4, 7.9 Hz, 1H), 4.37 (ddd, J=46.2,9.5, 6.3 Hz, 1H), 4.09 (br d, J=11.6 Hz, 1H), 3.68-3.78 (m, 2H),3.34-3.43 (br m, 1H), 3.08-3.16 (br m, 1H), 1.53 (s, 9H), 1.28 (d, J=6.1Hz, 3H).

Step 15. Synthesis of tert-butyl[(4S,4aR,6S,8aS)-8a-(2-fluoro-5-formylphenyl)-4-(fluoromethyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]carbamate(C102)

A solution of C101 (390 mg, 0.794 mmol) in diethyl ether (12 mL) wascooled to −78° C. and treated drop-wise with methyllithium (3.0 Msolution in 1,2-diethoxymethane, 0.79 mL, 2.37 mmol) over seven minutes.After 35 minutes, sec-butyllithium (1.4 M solution in cyclohexane, 0.62mL, 0.87 mmol) was added drop-wise over 6 minutes; stirring was thencontinued at −78° C. for 35 minutes. At this point,N-methyl-N-phenylformamide (0.29 mL, 2.35 mmol) was added drop-wise over4 minutes. The reaction mixture was stirred at −78° C. for 2.25 hours,and then quenched via addition of saturated aqueous ammonium chloridesolution (2.3 mL) and water (7.7 mL). The mixture was extracted fourtimes with ethyl acetate, and the combined organic layers were driedover sodium sulfate, filtered, and concentrated in vacuo. Silica gelchromatography (Gradient: 0% to 30% ethyl acetate in hexanes) providedthe product as a white foam. Yield: 272 mg, 0.617 mmol, 78%. ¹H NMR (500MHz, CDCl₃) δ 9.98 (s, 1H), 7.86-7.92 (m, 1H), 7.81 (br d, J=6.7 Hz,1H), 7.21-7.28 (m, 1H, assumed; partially obscured by solvent peak),4.54 (ddd, J=47.0, 9.4, 7.9 Hz, 1H), 4.37 (ddd, J=46.2, 9.5, 6.3 Hz,1H), 4.10-4.15 (m, 1H), 3.79 (d, J=11.3 Hz, 1H), 3.71-3.78 (m, 1H),3.31-3.39 (br m, 1H), 3.12-3.19 (br m, 1H), 1.53 (s, 9H), 1.5-1.66 (m,2H, assumed; partially obscured by water peak), 1.29 (d, J=6.2 Hz, 3H).

Step 16. Synthesis of tert-butyl[(4S,4aR,6S,8aS)-4-(fluoromethyl)-8a-(2-fluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]carbamate(C103)

A solution of 2,2,2-trifluoroethanamine (61 mg, 0.62 mmol) indichloromethane (0.5 mL) was added to a solution of C102 (135 mg, 0.31mmol) in dichloromethane (0.5 mL) and the reaction mixture was stirredfor 3 hours. Additional 2,2,2-trifluoroethanamine (61 mg, 0.62 mmol) wasadded, and stirring was continued for 2.5 hours, whereupon acetic acid(2 mL) was added. After 1.5 hours, 2,2,2-trifluoroethanamine (61 mg,0.62 mmol) was again introduced, followed by sodiumtriacetoxyborohydride (130 mg, 0.61 mmol). After 12 hours, the reactionmixture was diluted with saturated aqueous sodium bicarbonate solution(3 mL) and extracted three times with ethyl acetate. The combinedorganic layers were washed with saturated aqueous sodium chloridesolution, dried over sodium sulfate, filtered, and concentrated invacuo. Silica gel chromatography (Gradient: 0% to 30% ethyl acetate inhexanes) provided the product as a white foamy solid. Yield: 146 mg,0.279 mmol, 90%. ¹H NMR (500 MHz, CDCl₃) δ 7.31-7.35 (m, 1H), 7.21 (brd, J=6.5 Hz, 1H), 7.06 (dd, J=12.2, 8.3 Hz, 1H), 4.53 (ddd, J=47.0, 9.4,7.7 Hz, 1H), 4.36 (ddd, J=46.3, 9.5, 6.5 Hz, 1H), 4.16 (d, J=11.4 Hz,1H), 3.88 (s, 2H), 3.71-3.78 (m, 2H), 3.35-3.44 (m, 1H), 3.19 (q,J_(HF)=9.4 Hz, 2H), 3.14-3.21 (m, 1H), 1.53 (s, 9H), 1.5-1.67 (m, 2H,assumed; partially obscured by water signal), 1.29 (d, J=6.2 Hz, 3H).

Step 17. Synthesis of(4S,4aR,6S,8aS)-4-(fluoromethyl)-8a-(2-fluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine(19)

Compound C103 (145 mg, 0.277 mmol) was dissolved in dichloromethane (2mL) and treated with trifluoroacetic acid (1 mL). After 4 hours, thereaction mixture was quenched with saturated aqueous sodium bicarbonatesolution and extracted three times with dichloromethane. The combinedorganic layers were dried over sodium sulfate, filtered, concentrated invacuo, and purified by silica gel chromatography (Gradient: 0% to 10%methanol in dichloromethane). The material obtained from chromatographywas dissolved in acetonitrile and lyophilized, then subjected topreparative HPLC (Column: Phenomenex Luna C18(2), 15 μm; Mobile phase A:0.05% trifluoroacetic acid in water; Mobile phase B: 0.05%trifluoroacetic acid in acetonitrile; Gradient: 2% to 90% B). Thecombined product fractions were neutralized with solid sodiumbicarbonate, saturated with solid sodium chloride and extracted threetimes with ethyl acetate. The combined extracts were dried over sodiumsulfate, filtered, concentrated, and lyophilized to afford the productas a white solid. Yield: 31 mg, 73 μmol, 26%. LCMS m/z 424.2 [M+H]+. ¹HNMR (500 MHz, CDCl₃) δ 7.24-7.31 (m, 2H, assumed; partially obscured bysolvent peak), 7.04 (dd, J=12.3, 8.3 Hz, 1H), 4.57 (ddd, J=46.6, 9.5,6.7 Hz, 1H), 4.31-4.46 (m, J_(HF)=46.7 Hz, 1H), 4.12 (dd, J=11.4, 2.0Hz, 1H), 3.84-3.92 (m, 3H), 3.70-3.78 (m, 1H), 3.47-3.56 (m, 1H), 3.18(q, J_(HF)=9.4 Hz, 2H), 3.08-3.14 (m, 1H), 1.44-1.6 (m, 2H, assumed;partially obscured by water peak), 1.28 (d, J=6.2 Hz, 3H).

Example 20(4S,4aR,6S,8aS)-8a-(2,4-Difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-4-(fluoromethyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine(20)

Step 1. Synthesis of(3R,3aR,5S)-3-[(benzyloxy)methyl]-5-methyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole(C104)

A solution of C92 (65.7 g, 384 mmol) in tetrahydrofuran (500 mL) wasadded drop-wise over 25 minutes to a mixture of sodium hydride (60% inoil, 22.9 g, 572 mmol) in tetrahydrofuran (200 mL) that was cooled in anice/salt/water bath. Additional tetrahydrofuran (200 mL) was used torinse the addition funnel and facilitate stirring, which was continuedunder cooling. After 1 hour, benzyl bromide (98.4 g, 575 mmol) was addeddrop-wise over 15 minutes; at the completion of the addition, the icebath was removed, then reapplied as needed as the reaction mixture beganto exotherm. After 1.5 hours, the reaction was slowly quenched withwater (650 mL), then diluted with ethyl acetate (650 mL) and allowed tostand for 18 hours. The aqueous layer was extracted with ethyl acetate(2×350 mL), and the combined organic layers were dried over magnesiumsulfate (100 g), filtered, and concentrated in vacuo. Silica gelchromatography (Eluents: heptane, followed by 10%, 20% and 30% ethylacetate in heptane) provided the product. Yield: 76.4 g, 292 mmol, 76%.LCMS m/z 261.8 [M+H⁺]. ¹H NMR (500 MHz, CDCl₃) δ 7.3-7.4 (m, 5H), 4.63(d, J=13.4 Hz, 1H), 4.61 (AB quartet, J_(AB)=12.1 Hz, Δν_(AB)=6.8 Hz,2H), 4.29 (ddd, J=10.2, 4.8, 4.8 Hz, 1H), 4.15 (dd, J=13.4, 1.2 Hz, 1H),3.74 (dd, half of ABX pattern, J=10.5, 4.7 Hz, 1H), 3.71 (dd, half ofABX pattern, J=10.6, 4.7 Hz, 1H), 3.54-3.65 (m, 1H), 3.30 (ddd, J=11.1,10.9, 6.6 Hz, 1H), 2.09 (ddd, J=12.9, 6.6, 1.6 Hz, 1H), 1.49 (ddd,J=12.8, 11.4, 11.4 Hz, 1H), 1.24 (d, J=6.2 Hz, 3H).

Step 2. Synthesis of(3R,3aR,5S,7aS)-3-[(benzyloxy)methyl]-7a-(5-bromo-2,4-difluorophenyl)-5-methylhexahydro-1H-pyrano[3,4-c][1,2]oxazole(C105)

Reaction of C104 with 1-bromo-2,4-difluoro-5-iodobenzene was carried outusing the method described for synthesis of C29 in Example 10. Theproduct was obtained as a white solid. Yield: 1.31 g, 2.88 mmol, 25%. ¹HNMR (500 MHz, CDCl₃) δ 8.14 (dd, J=8.2, 8.2 Hz, 1H), 7.24-7.33 (m, 3H,assumed; partially obscured by solvent peak), 7.12-7.18 (m, 2H), 6.73(dd, J=11.2, 8.0 Hz, 1H), 6.31 (s, 1H), 4.30 (AB quartet, J_(AB)=12.1Hz, Δν_(AB)=89 Hz, 2H), 4.08 (ddd, J=6.6, 6.1, 1.4 Hz, 1H), 3.88 (dd,J=12.8, 2.0 Hz, 1H), 3.76 (d, J=13 Hz, 1H), 3.60-3.72 (m, 1H), 3.05-3.14(m, 1H), 3.00 (dd, J=9.9, 6.1 Hz, 1H), 2.75 (dd, J=9.9, 6.7 Hz, 1H),2.03 (ddd, J=14.2, 7.6, 2.0 Hz, 1H), 1.40-1.53 (m, 1H), 1.24 (d, J=6.2Hz, 3H).

Step 3. Synthesis of(1R)-1-[(2S,4R,5S)-5-amino-5-(5-bromo-2,4-difluorophenyl)-2-methyltetrahydro-2H-pyran-4-yl]-2-(benzyloxy)ethanol(C106)

Molybdenum hexacarbonyl (1.79 g, 6.78 mmol) was added to a solution ofC105 (2.80 g, 6.16 mmol) in acetonitrile (36 mL) and water (3.6 mL), andthe reaction mixture was heated at reflux for 30 minutes, then cooled toroom temperature. Sodium borohydride (466 mg, 12.3 mmol) was added, andthe reaction mixture was heated at reflux for 4 hours, whereupon it wasallowed to cool to room temperature, and was then quenched withmethanol. The mixture was filtered through diatomaceous earth, and thefilter pad was rinsed sequentially with methanol and with ethyl acetate.The filtrate was concentrated in vacuo and then partitioned betweenethyl acetate and saturated aqueous sodium bicarbonate solution. Theaqueous layer was extracted three times with ethyl acetate, and thecombined organic layers were washed with saturated aqueous sodiumchloride solution, dried over sodium sulfate, filtered, and concentratedin vacuo. The residue was suspended in dichloromethane (50 mL), treatedwith aqueous sodium hydroxide solution (1 M, 30 mL) and stirred at roomtemperature for 1.5 hours. Water (50 mL) was added, and the aqueouslayer was extracted with dichloromethane (2×30 mL); the combined organiclayers were washed with saturated aqueous sodium chloride solution,dried over sodium sulfate, filtered, and concentrated under reducedpressure. Silica gel chromatography (Gradient: 0% to 60% ethyl acetatein hexanes) afforded the product as a colorless oil. Yield: 2.52 g, 5.52mmol, 90%. ¹H NMR (500 MHz, CDCl₃) δ 8.00 (dd, J=8.1, 8.1 Hz, 1H),7.27-7.36 (m, 3H), 7.18-7.24 (m, 2H), 6.76 (dd, J=11.8, 8.1 Hz, 1H),4.32 (AB quartet, J_(AB)=11.9 Hz, Δν_(AB)=9.8 Hz, 2H), 3.94 (dd, J=11.4,1.8 Hz, 1H), 3.58-3.72 (m, 2H), 3.26 (d, J=11.4 Hz, 1H), 3.05-3.15 (m,2H), 2.73 (ddd, J=12.5, 4.6, 4.6 Hz, 1H), 1.61-1.74 (m, 1H), 1.5-1.61(m, 1H, assumed; partially obscured by water peak), 1.27 (d, J=6.1 Hz,3H).

Step 4. Synthesis ofN-{[(3S,4R,6S)-4-[(1R)-2-(benzyloxy)-1-hydroxyethyl]-3-(5-bromo-2,4-difluorophenyl)-6-methyltetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide(C107)

Compound C106 was converted to the product according to the methoddescribed for synthesis of C97 in Example 19. The product was obtainedas a white foam. Yield: 3.07 g, 4.96 mmol, 90%. LCMS m/z 621.3 [M+H⁺].

Step 5. Synthesis ofN-[(4S,4aR,6S,8aS)-4-[(benzyloxy)methyl]-8a-(5-bromo-2,4-difluorophenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C108)

Compound C107 was converted to the product according to the methoddescribed for synthesis of C78 in Example 17. The product was isolatedas a white foam. Yield: 2.62 g, 4.36 mmol, 88%. LCMS m/z 601.4, 603.1[M+H⁺]. ¹H NMR (500 MHz, CDCl₃) δ 8.07-8.31 (m, 2H), 7.48-7.57 (m, 2H),7.41-7.48 (m, 2H), 7.27-7.39 (m, 5H), 6.95 (dd, J=11.7, 7.8 Hz, 1H),4.49 (AB quartet, J_(AB)=11.9 Hz, ν_(AB)=46.4 Hz, 2H), 4.03-4.11 (m,1H), 3.77 (d, J=12.0 Hz, 1H), 3.63-3.74 (m, 2H), 3.48 (dd, J=9.1, 7.9Hz, 1H), 3.35-3.45 (m, 1H), 3.07-3.18 (m, 1H), 1.5-1.64 (m, 1H, assumed;partially obscured by water peak), 1.40-1.49 (m, 1H), 1.23 (d, J=6.1 Hz,3H).

Step 6. Synthesis ofN-[(4S,4aR,6S,8aS)-8a-(5-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C109)

Trifluoromethanesulfonic acid (1.2 mL, 14 mmol) was added to a solutionof C108 (2.62 g, 4.36 mmol) in dichloromethane (40 mL). The reactionmixture was stirred at room temperature for 2.5 hours, then cooled to 0°C. and basified to pH 12 with 1 M aqueous sodium hydroxide solution. Theresulting solution was partitioned between water (50 mL) anddichloromethane (50 mL), and the aqueous layer was extracted withdichloromethane (2×30 mL); the combined organic layers were washed withsaturated aqueous sodium chloride solution (30 mL), dried over sodiumsulfate, filtered, and concentrated in vacuo. Trituration with 20% ethylacetate in hexanes provided the product as a white solid. Yield: 2.10 g,4.11 mmol, 94%. LCMS m/z 511.1 [M+H⁺]. ¹H NMR (500 MHz, CDCl₃) δ 8.20(br s, 2H), 7.50-7.59 (m, 2H), 7.42-7.49 (m, 2H), 6.95 (dd, J=11.7, 7.8Hz, 1H), 4.05-4.17 (m, 1H), 3.66-3.92 (m, 5H), 3.26-3.39 (m, 1H),3.09-3.26 (m, 1H), 1.60-1.68 (m, 2H), 1.27 (d, J=6.2 Hz, 3H).

Step 7. Synthesis ofN-[(4S,4aR,6S,8aS)-8a-(5-bromo-2,4-difluorophenyl)-4-(fluoromethyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C110)

To a suspension of C109 (500 mg, 0.98 mmol) in dichloromethane (10 mL)at −78° C. was added (diethylamino)sulfur trifluoride (0.14 mL, 1.1mmol), and the reaction mixture was allowed to stir at −78° C. for 10minutes before being allowed to warm to room temperature. After 2 hoursat room temperature, the reaction was quenched with saturated aqueoussodium bicarbonate solution, diluted with water, and extracted withdichloromethane (3×50 mL). The combined organic layers were washed withsaturated aqueous sodium chloride solution (50 mL), dried over sodiumsulfate, filtered, and concentrated in vacuo. Silica gel chromatography(Gradient: 0% to 30% ethyl acetate in hexanes) afforded the product as acolorless oil/foam. Yield: 123 mg, 0.240 mmol, 24%. ¹H NMR (300 MHz,CDCl₃) δ 8.02-8.32 (m, 2H), 7.42-7.61 (m, 4H), 6.98 (dd, J=11.7, 7.8 Hz,1H), 4.58 (ddd, J=47, 9.4, 8.0 Hz, 1H), 4.43 (ddd, J=46, 9.5, 6.3 Hz,1H), 4.11 (br d, J=12.6 Hz, 1H), 3.80 (d, J=12.0 Hz, 1H), 3.67-3.85 (m,1H), 3.39-3.58 (m, 1H), 3.10-3.25 (m, 1H), 1.6-1.71 (m, 2H, assumed;partially obscured by solvent peak), 1.29 (d, J=6.2 Hz, 3H).

Step 8. Synthesis ofN-[(4S,4aR,6S,8aS)-8a-(2,4-difluoro-5-formylphenyl)-4-(fluoromethyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C111)

Compound C110 was converted to the product using the method describedfor synthesis of C102 in Example 19. The product was obtained as acolorless oil. Yield: 23 mg, 50 μmol, 21%. Also isolated was unreactedC110 (17 mg, 33 μmol). C111: LCMS m/z 463.1 [M+H]+. ¹H NMR (300 MHz,CDCl₃) δ 10.24 (s, 1H), 8.12 (br d, J=7.3 Hz, 2H), 7.90 (dd, J=8.7, 7.9Hz, 1H), 7.52-7.61 (m, 1H), 7.41-7.52 (m, 2H), 7.01 (dd, J=11.8, 9.6 Hz,1H), 4.58 (ddd, J=47, 9.4, 8.2 Hz, 1H), 4.41 (ddd, J=46, 9.5, 6.2 Hz,1H), 4.03-4.13 (m, 1H), 3.82 (d, J=11.8 Hz, 1H), 3.69-3.88 (m, 1H),3.35-3.54 (m, 1H), 3.10-3.26 (m, 1H), 1.55-1.72 (m, 2H, assumed;partially obscured by water peak), 1.29 (d, J=6.1 Hz, 3H).

Step 9. Synthesis ofN-[(4S,4aR,6S,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-4-(fluoromethyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide(C112)

To a solution of C111 (22 mg, 48 μmol) in dichloromethane (0.5 mL) wasadded 2,2,2-trifluoroethanamine (23 μL, 0.29 mmol), followed by sodiumtriacetoxyborohydride (21 mg, 99 μmol), and the reaction flask wassealed and stirred at room temperature for 18 hours. After beingquenched with saturated aqueous sodium bicarbonate solution (3 mL), thereaction mixture was diluted with water (20 mL) and extracted withdichloromethane (3×10 mL). The combined organic layers were washed withsaturated aqueous sodium chloride solution, dried over sodium sulfate,filtered, and concentrated in vacuo. Silica gel chromatography(Gradient: 0% to 50% ethyl acetate in hexanes) afforded the product as acolorless oil. Yield: 16 mg, 29 μmol, 60%. LCMS m/z 546.2 [M+H]+. ¹H NMR(500 MHz, CDCl₃) δ 8.15-8.25 (m, 2H), 7.53 (br t, J=7.3 Hz, 1H), 7.46(br dd, J=7.7, 7.3 Hz, 2H), 7.37 (dd, J=8.4, 8.4 Hz, 1H), 6.89 (dd,J=11.9, 9.2 Hz, 1H), 4.58 (ddd, J=46.9, 9.4, 7.8 Hz, 1H), 4.42 (ddd,J=46.2, 9.5, 6.5 Hz, 1H), 4.11-4.16 (m, 1H), 3.84-3.95 (m, 2H),3.71-3.83 (m, 2H), 3.43-3.56 (m, 1H), 3.10-3.27 (m, 3H), 1.6-1.74 (m,2H, assumed; partially obscured by solvent peak), 1.29 (d, J=6.1 Hz,3H).

Step 10. Synthesis of(4S,4aR,6S,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-4-(fluoromethyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine(20)

A mixture of C112 (16 mg, 29 μmol), pyridine (24 μL, 0.30 mmol) andmethoxylamine hydrochloride (24.5 mg, 0.29 mmol) in ethanol (1 mL) washeated at 50° C. for 15 hours. The reaction mixture was allowed to coolto room temperature, whereupon it was concentrated in vacuo; the residuewas purified via preparative HPLC (Column: Phenomenex Luna C18(2), 15μm; Mobile phase A: 0.05% trifluoroacetic acid in water; Mobile phase B:0.05% trifluoroacetic acid in acetonitrile; Gradient: 2% to 90% B). Thefractions containing product were pooled, neutralized with solid sodiumbicarbonate, saturated with solid sodium chloride, and extracted threetimes with ethyl acetate. The combined organic layers were dried oversodium sulfate, filtered, and concentrated under reduced pressure; theresidue was dissolved in acetonitrile and lyophilized to afford theproduct as a white solid. Yield: 7.4 mg, 17 μmol, 59%. APCI m/z 442.3[M+H]+. ¹H NMR (500 MHz, CDCl₃) δ 7.37 (br dd, J=8.6, 8.5 Hz, 1H), 6.84(dd, J=11.9, 9.3 Hz, 1H), 4.59 (ddd, J=46.5, 9.5, 6.6 Hz, 1H), 4.35-4.49(m, 1H), 4.04 (dd, J=11.6, 1.8 Hz, 1H), 3.88-3.97 (m, 3H), 3.69-3.77 (m,1H), 3.51-3.60 (m, 1H), 3.07-3.25 (m, 3H), 1.45-1.6 (m, 2H, assumed;partially obscured by solvent peak), 1.29 (d, J=6.2 Hz, 3H).

Biological Assays

BACE1 Cell-Free Assay:

Beta-secretase (BACE) is one of the enzymes involved in the generationof the amyloid beta peptide found in the amyloid plaques of Alzheimer'sDisease patients. This assay measures the inhibition of thebeta-secretase enzyme as it cleaves a non-native peptide.

A synthetic APP substrate that can be cleaved by beta-secretase havingN-terminal biotin and made fluorescent by the covalent attachment ofOregon Green at the Cys residue is used to assay beta-secretase activityin the presence or absence of the inhibitory compounds. The substrate isBiotin-GLTNIKTEEISEISŶEVEFR-C[Oregon Green]KK-OH. The BACE1 enzyme isaffinity purified material from conditioned media of CHO-K1 cells thathave been transfected with a soluble BACE construct (BACE1deltaTM96His).Compounds are incubated in a ½ log dose response curve from a topconcentration of 100 μM with BACE1 enzyme and the biotinylatedfluorescent peptide in 384-well black plates (Thermo Scientific #4318).BACE1 is at a final concentration of 0.1 nM with a final concentrationof peptide substrate of 150 nM in a reaction volume of 30 μL assaybuffer (100 mM sodium acetate, pH 4.5 (brought to pH with acetic acid),and 0.001% Tween-20). Plates are covered and incubated for 3 hours at37° C. The reaction is stopped with the addition of 30 μL of 1.5 μMStreptavidin (Pierce, #21125). After a 10 minute incubation at roomtemperature, plates are read on a PerkinElmer EnVision for fluorescencepolarization (Ex485 nm/Em530 nm). The activity of the beta-secretaseenzyme is detected by changes in the fluorescence polarization thatoccur when the substrate is cleaved by the enzyme. Incubation in thepresence of compound inhibitor demonstrates specific inhibition ofbeta-secretase enzymatic cleavage of the synthetic APP substrate.

Whole Cell Assay (In Vitro sAPPb Assay):

H4 human neuroglioma cells over-expressing the wild-type human APP₆₉₅are treated for 18 hours with compound in cell growth media having afinal concentration 1% DMSO. sAPPI3 levels are measured using eitherTMB-ELISA or Pierce SuperSignal ELISA Pico Chemiluminescent Substrate(Pierce 37069) with capture APP N-terminal antibody (AffinityBioReagents, OMA1-03132), wild-type sAPPI3 specific reporter p192(Elan), and tertiary anti rabbit-HRP (GE Healthcare).

BACE2 Assay:

This assay measures the inhibition of the BACE2 enzyme as it cleaves anon-native peptide. A synthetic substrate that can be cleaved by BACE2having N-terminal biotin and made fluorescent by the covalent attachmentof Oregon Green at the Cys residue is used to assay BACE2 activity inthe presence or absence of the inhibitory compounds. The substrate isBiotin-KEISEISYEVEFR-C(Oregon green)-KK-OH. The BACE2 enzyme isavailable from Enzo Life Sciences (Cat #BML-SE550). Compounds areincubated in a log dose response curve from a top concentration of 100μM with BACE2 enzyme and the biotinylated fluorescent peptide in384-well black plates (Thermo Scientific #4318). BACE2 is at a finalconcentration of 2.5 nM with a final concentration of peptide substrateof 150 nM in a reaction volume of 30 μL assay buffer (100 mM sodiumacetate, pH 4.5 (brought to pH with acetic acid), and 0.001% Tween-20).Plates are covered and incubated for 3 hours at 37° C. The reaction isstopped with the addition of 30 μL of 1.5 μM Streptavidin (Pierce,#21125). After a 10 minute incubation at room temperature, plates areread on a PerkinElmer EnVision for fluorescence polarization (Ex485nm/Em530 nm). The activity of the beta-secretase enzyme is detected bychanges in the fluorescence polarization that occur when the substrateis cleaved by the enzyme. Incubation in the presence of compoundinhibitor demonstrates specific inhibition of BACE2 enzymatic cleavageof the synthetic substrate.

TABLE 1 Biological Data BACE1 BACE2 Cell-free sAPPβ Whole- Cell-freeExample Assay Cell Assay Assay # IC₅₀ (μM)^(a) IC₅₀ (nM)^(a) IC₅₀ (μM) 11.22 53.5 N.D.^(c) 2 0.445 74.0 2.80^(a) 3 5.55 393 N.D. 4 0.854 93.02.52^(b) 5 0.320 46.5 N.D. 6 2.33 195 N.D. 7 1.78 119 N.D. 8 0.076 5.9N.D. 9 0.076 8.94 N.D. 10 0.064 10.9 N.D. 11 0.107 12.1 N.D. 12 0.0606.43 N.D. 13 0.342 47.6 N.D. 14 0.967 49.6 N.D. 15 0.376 8.05 0.423^(d)16 0.019 1.88 0.108^(d) 17 0.082 11.4^(d) N.D. 18 0.036 0.545 0.020^(d)19 0.150 30.4 N.D. 20 0.068 35.7 N.D. ^(a)Reported IC₅₀ values are thegeometric mean of 2-3 determinations. ^(b)IC₅₀ value is from a singledetermination. ^(c)“N.D.” means “no data”. ^(d)Reported IC₅₀ value isthe geometric mean of 4-7 determinations.

1. A method of treating Alzheimer's disease in a patient, the methodcomprising administering a therapeutically effective amount of acompound of Formula I,

Wherein R¹ is hydrogen or methyl, wherein said methyl is optionallysubstituted with one to three substituents independently selected fromhalogen or methoxy; R² is C₁₋₆ alkyl, —(C(R⁵)₂)_(m)—(C₃₋₆ cycloalkyl),—(C(R⁵)₂)_(m)—(C₆₋₁₀ aryl), —(C(R⁵)₂)_(m)-(5- to 10-membered heteroaryl)or —(C(R⁵)₂)_(t)—OR⁶; wherein said alkyl, cycloalkyl, aryl or heteroarylmoieties are optionally substituted with one to three substituentsindependently selected from halogen, C₁₋₆ alkyl, —CH₂F, —CHF₂, —CF₃, —CNor —OR⁷; R³ is —(C(R⁵)₂)_(m)—(CN) or —(C(R⁵)₂)_(n)—(NHR⁷); R⁴ isindependently selected from halogen, C₁₋₆ alkyl or C₁₋₆ alkoxy; whereinsaid alkyl or alkoxy is optionally substituted with one to three fluoro;R⁵ at each occurrence is independently selected from hydrogen or C₁₋₃alkyl, wherein said alkyl is optionally substituted with one to threehalogen; R⁶ is hydrogen, C₁₋₆ alkyl or —(C(R⁵)₂)_(n)—(C₆₋₁₀ aryl),wherein said alkyl and aryl are optionally substituted with one to threesubstituents independently selected from halogen, C₁₋₃ alkyl, —CH₂F,—CHF₂, —CF₃, —CN or —OH; R⁷ for each occurrence is hydrogen or C₁₋₆alkyl, wherein said alkyl is optionally substituted with one to threesubstituents independently selected from halogen or C₁₋₆ alkoxy; m ateach occurrence is independently 0, 1 or 2; n at each occurrence isindependently is 1 or 2; t is 1 or 2; and x is 0, 1,2 or 3; or atautomer thereof or a pharmaceutically acceptable salt of said compoundor tautomer; to a patient in need of treatment thereof.
 2. The method ofclaim 1 wherein R³ is —(C(R⁵)₂)_(m)—(CN); m is 0 or 1; and R⁵ at eachoccurrence is hydrogen; or a tautomer thereof or a pharmaceuticallyacceptable salt of said compound or tautomer.
 3. The method of claim 1wherein R³ is —(C(R⁵)₂)_(n)—(NHR⁷); n is 1; and R⁵ at each occurrence ishydrogen; or a tautomer thereof or a pharmaceutically acceptable salt ofsaid compound or tautomer.
 4. The method of claim 1 wherein m is 0; R²is C₁₋₆ alkyl optionally substituted with one to three fluoro, or—(C(R⁵)₂)_(t)—OR⁶; wherein t is 1; R⁵ at each occurrence is hydrogen,and R⁶ is C₁₋₃ alkyl optionally substituted with one to three fluoro, or—(C(R⁵)₂)_(n)—(C₆₋₁₀ aryl), wherein said aryl is optionally substitutedwith one to three substituents selected from halogen, C₁₋₆ alkyl, —CH₂F,—CHF₂, —CF₃, —CN or —OH; or a tautomer thereof or a pharmaceuticallyacceptable salt of said compound or tautomer.
 5. The method of claim 4wherein R⁶ is —(C(R⁵)₂)_(n)—(C₆₋₁₀ aryl), said aryl is phenyl optionallysubstituted with one to three substituents independently selected fromhalogen, C₁₋₆ alkyl, —CH₂F, —CHF₂, —CF₃, —CN or —OH; n is 1; and R⁵ ateach occurrence is hydrogen; or a tautomer thereof or a pharmaceuticallyacceptable salt of said compound or tautomer.
 6. The method of claim 1wherein R² is —(C(R⁵)₂)_(m)—(C₃₋₆ cycloalkyl) or —(C(R⁵)₂)_(m)-(5- to10-membered heteroaryl), wherein said cycloalkyl or heteroaryl isoptionally substituted with one to three substituents independentlyselected from halogen, C₁₋₆ alkyl, —CH₂F, —CHF₂, and —CF₃ m is 0; and R⁵at each occurrence is hydrogen; or a tautomer thereof or apharmaceutically acceptable salt of said compound or tautomer.
 7. Themethod of claim 1 wherein R⁴ is independently selected from fluoro,chloro, methyl, ethyl, propyl, methoxy or ethoxy; wherein said methyl,ethyl and propyl groups are optionally substituted with one to threefluoro; and x is 0, 1 or 2; or a tautomer thereof or a pharmaceuticallyacceptable salt of said compound or tautomer.
 8. A method of treatingAlzheimer's disease in a patient, the method comprising administering atherapeutically effective amount of a compound of claim 1 of Formula Ia,

wherein R¹ is hydrogen or methyl, wherein said methyl is optionallysubstituted with one to three halogen; R² is C₁₋₆ alkyl,—(C(R⁵)₂)_(m)—(C₃₋₆ cycloalkyl), —(C(R⁵)₂)_(m)-(5- to 10-memberedheteroaryl) or —(C(R⁵)₂)_(t)—OR⁶; wherein said alkyl, cycloalkyl orheteroaryl moieties are optionally substituted with one to threesubstituents independently selected from halogen, C₁₋₆ alkyl, —CH₂F,—CHF₂, —CF₃, —CN or —OH; R⁴ is independently halogen, C₁₋₆ alkyl or C₁₋₆alkoxy; wherein said alkyl or alkoxy moieties are optionally substitutedwith one to three fluoro; R⁵ at each occurrence is hydrogen or C₁₋₃alkyl, wherein said alkyl is optionally substituted with one to threehalogen; R⁶ is hydrogen, C₁₋₆ alkyl or —(C(R⁵)₂)_(n)—(C₆₋₁₀ aryl),wherein said alkyl and aryl are optionally substituted with one to threesubstituents selected from halogen, C₁₋₃ alkyl, —CH₂F, —CHF₂, —CF₃, —CNor —OH; m is 0, 1 or 2; n is 1 or 2; t is 1 or 2; and x is 0, 1 or 2 or3; or a tautomer thereof or a pharmaceutically acceptable salt of saidcompound or tautomer; to a patient in need of treatment thereof.
 9. Themethod of claim 8 wherein R⁴ is independently selected from fluoro,chloro, methyl, ethyl, propyl, methoxy and ethoxy, wherein said methyl,ethyl and propyl groups are optionally substituted with one to threefluoro; and x is 0, 1 or 2; or a tautomer thereof or a pharmaceuticallyacceptable salt of said compound or tautomer.
 10. The method of claim 9wherein R² is methyl, optionally substituted with one to three fluoro;R⁴ is independently selected from methoxy, chloro or fluoro; and x is 0,1 or 2; or a tautomer thereof or a pharmaceutically acceptable salt ofsaid compound or tautomer.
 11. The method of claim 9 wherein R² is—(C(R⁵)₂)_(m)-(5-membered heteroaryl); R⁴ is independently methoxy,chloro or fluoro; m is 0; and x is 0, 1 or 2; or a tautomer thereof or apharmaceutically acceptable salt of said compound or tautomer.
 12. Themethod of claim 9 wherein R² is —(C(R⁵)₂)_(t)—OR⁶; R⁶ is hydrogen,methyl or —(C(R⁵)₂)_(n)—(C₆₋₁₀ aryl), wherein the aryl of R⁶ is phenyloptionally substituted with one to three substituents selected fromhalogen, C₁₋₃ alkyl, —CH₂F, —CHF₂, —CF₃, —CN or —OH; R⁴ is independentlymethoxy, chloro or fluoro; x is 0, 1 or 2; n is 1; and t is 1; or atautomer thereof or a pharmaceutically acceptable salt of said compoundor tautomer.
 13. The method of claim 9 wherein R² is —(C(R⁵)₂)_(m)—(C₃₋₆cycloalkyl), wherein said cycloalkyl is optionally substituted with oneto three substituents selected from halogen or C₁₋₆ alkyl, optionallysubstituted with one to three fluoro; R⁴ is independently methoxy,chloro or fluoro; m is 0 or 1; and x is 0, 1 or 2; or a tautomer thereofor a pharmaceutically acceptable salt of said compound or tautomer. 14.A method of treating Alzheimer's disease in a patient, the methodcomprising administering a therapeutically effective amount of acompound of claim 1 of Formula Ib

wherein R¹ is hydrogen or methyl, wherein said methyl is optionallysubstituted with one to three halogen; R² is C₁₋₆ alkyl,—(C(R⁵)₂)_(m)—(C₃₋₆ cycloalkyl), —(C(R⁵)₂)_(m)-(5- to 10-memberedheteroaryl) or —(C(R⁵)₂)_(t)—OR⁶; wherein said alkyl, cycloalkyl orheteroaryl moieties are optionally substituted with one to threesubstituents independently selected from halogen, C₁₋₆ alkyl, —CH₂F,—CHF₂, —CF₃, —CN or —OH; R⁴ is independently halogen, C₁₋₆ alkyl or C₁₋₆alkoxy; wherein said alkyl or alkoxy is optionally substituted with oneto three fluoro; R⁵ at each occurrence is hydrogen or C₁₋₃ alkyl,wherein said alkyl is optionally substituted with one to three halogen;R⁶ is hydrogen, C₁₋₆ alkyl or —(C(R⁵)₂)_(n)—(C₆₋₁₀ aryl), wherein saidalkyl and aryl are optionally substituted with one to three substituentsselected from halogen, C₁₋₃ alkyl, —CH₂F, —CHF₂, —CF₃, —CN or —OH; R⁷for each occurrence is hydrogen or C₁₋₆ alkyl optionally substitutedwith one to three halogen; m is 0, 1 or 2; n is 1 or 2; t is 1 or 2; andx is 0, 1, 2 or 3; or a tautomer thereof or a pharmaceuticallyacceptable salt of said compound or tautomer.
 15. The method of claim 14wherein R⁷ is ethyl optionally substituted with one to three fluoro; ora tautomer thereof or a pharmaceutically acceptable salt of saidcompound or tautomer.
 16. The method of claim 15 wherein R² is C₁₋₃alkyl optionally substituted with one to three fluoro; R⁴ isindependently fluoro, chloro or methoxy; x is 0, 1 or 2; or a tautomerthereof or a pharmaceutically acceptable salt of said compound ortautomer.
 17. The method according to claim 1, or a tautomer thereof ora pharmaceutically acceptable salt of said compound or tautomer; whereinR¹ is hydrogen or fluoromethyl; R² is methyl, fluoromethyl, or1-methyl-1H-pyrazol-4-yl; and R³ is (2,2,2-trifluoroethyl)aminomethyl or(1-methoxypropan-2-yl)aminomethyl.
 18. The method according to claim 17,or a tautomer thereof or a pharmaceutically acceptable salt of saidcompound or tautomer; wherein R⁴ is fluoro; and x is 1 or
 2. 19. Themethod according to claim 18 wherein the compound is selected from thegroup consisting of(4aR,6R,8aS)-6-(Fluoromethyl)-8a-(2-fluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine;rel-(4aR,6R,8aS)-8a-(2-Fluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine;(4aR*,6R*,8aS*)-8a-[2-Fluoro-5-({[(2R)-1-methoxypropan-2-yl]amino}methyl)phenyl]-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine;(4S,4aR,6S,8aS)-4-(Fluoromethyl)-8a-(2-fluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine;(4S,4aR,6S,8aS)-8a-(2,4-Difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-4-(fluoromethyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine;or a tautomer thereof or a pharmaceutically acceptable salt of saidcompound or tautomer.
 20. The method according to claim 1, or a tautomerthereof or a pharmaceutically acceptable salt of said compound ortautomer; wherein R¹ is hydrogen or methyl; R² is methyl, fluoromethyl,hydroxymethyl, methoxymethyl, benzyloxymethyl, cyclopropyl,3-methyl-1,2-oxazol-5-yl, 4-methyl-1,3-oxazol-2-yl or1-methyl-1H-pyrazol-4-yl; R³ is —CN; R⁴ is independently fluoro, chloroor methoxy; and x is 0, 1 or
 2. 21. The method according to claim 20wherein the compound is selected from the group consisting of5-[(4aR,6R,8aS)-2-Amino-6-[(benzyloxy)methyl]-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluoro-2-methoxybenzonitrile;5-[(4aR,6R,8aS)-2-Amino-6-[(benzyloxy)methyl]-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzonitrile;5-[(4aR,6R,8aS)-2-Amino-6-(hydroxymethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzonitrile;5-[(4aR,6R,8aS)-2-Amino-6-(fluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzonitrile;5-[(4aR,6R,8aS)-2-Amino-6-(methoxymethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzonitrile;3-[(4aR,6S,8aS)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-chlorobenzonitrile;3-[(4aR,6S,8aS)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]benzonitrile;3-[(4aR,6R,8aS)-2-Amino-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile;3-[(4aR,6R,8aS)-2-Amino-6-(4-methyl-1,3-oxazol-2-yl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile;3-[(4aR,6R,8aS)-2-Amino-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile;3-[(4aR,6R,8aS)-2-Amino-6-cyclopropyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile;3-[(4aR,6S,8aS)-2-Amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile;and3-[(4R,4aR,6R,8aS)-2-Amino-4-methyl-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluorobenzonitrile;or a tautomer thereof or a pharmaceutically acceptable salt of saidcompound or tautomer. 22.-24. (canceled)